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Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.
Itraconazole is a broad-spectrum orally active triazole antifungal used for both prophylaxis and treatment of systemic fungal infections (1, 2). Itraconazole exerts antifungal activity through the inhibition of fungal cytochrome P450 (CYP) 3A isoenzymes, which mediate the synthesis of ergosterol, a vital component of the fungal cell membrane (3). Itraconazole undergoes extensive hepatic metabolism by human CYP3A4 isoenzymes. Both itraconazole and its major active metabolite, hydroxyitraconazole, inhibit mammalian CYP3A4, although to a lesser extent than that with the fungal CYP3A isoenzymes (4).
Itraconazole is currently available as oral capsules in two marketed formulations: Sporanox, the brand product (Janssen Pharmaceuticals, Inc. [5]), and SUBA-itraconazole, the alternative product. SUBA-itraconazole is a novel formulation containing a solid dispersion of itraconazole in a pH-dependent polymeric matrix to enhance its dissolution and intestinal absorption; therefore, it exhibits greater bioavailability than the innovator product. As of 30 June 2015, SUBA-itraconazole has marketing approval in Australia, Spain, Germany, Sweden, and United Kingdom; currently, it is available in Australia under the trade name Lozanoc (Mayne Pharma International Pty Ltd. [6]), and in Spain under the trade name Itragerm.
Itraconazole is a weakly basic Biopharmaceutics Classification System (BCS) class II (low solubility/high permeability) drug that has a pH-dependent dissolution (pKa value, 3.7) and thus typically requires an acidic gastric environment for sufficient drug dissolution and adequate absorption. The coadministration of itraconazole with agents that inhibit gastric acidity, such as antacids and proton pump inhibitors, reduce the extent of itraconazole absorption (7, 8).
The pharmacokinetics of itraconazole is complex and highly variable, especially after oral administration. Both itraconazole and hydroxyitraconazole have nonlinear kinetics in a comparison of single- versus multiple-dose administration (9, 10). Various literature studies of the effect of food on itraconazole absorption showed that the absorption is highly varied between subjects, with considerable interstudy variability in the observed area under the concentration-time curve (AUC) values in the fed and fasted states (e.g., see references 11–14).
The primary aim of the present analysis was to develop a population pharmacokinetic model for itraconazole and hydroxyitraconazole that could effectively describe pharmacokinetic data from single-dose and multidose studies for SUBA-itraconazole and Sporanox, with particular emphasis on quantifying the effects of food and formulation on oral absorption and their implications on itraconazole exposure metrics.
Pharmacokinetic data.The pharmacokinetic data used in the analysis were collated data from seven different trials comparing SUBA-itraconazole with Sporanox in healthy subjects conducted by Mayne Pharma International. The designs and dosing schedules are summarized in Table 1. Two of the studies were conducted in the United Kingdom, and five studies were conducted in the United States. Overall, there were 238 subjects providing a total of 24,965 plasma concentrations, with an average of 105 observations per subject over 2 to 4 treatment periods. The studies differed by the country of origin of the reference Sporanox (sourced from the United States or the United Kingdom).
All studies were randomized crossover design studies with either four or two treatment periods per subject for the single-dose and multidose studies, respectively. Plasma concentrations were available for a range of doses for single-dose administration, in both fed and fasted states, and multidose administration in the fed state only.
The single-dose studies (HGN007, HGN008, MPG009, 10850702, and 10850703) compared either 50, 65, or 100 mg of SUBA-itraconazole with 100 or 200 mg of Sporanox administered once daily in the fed and fasted states. Itraconazole formulations were administered to subjects following an overnight fast of ≥10 h for the fasted periods and following a standardized high-fat high-calorie breakfast for the fed periods. All itraconazole doses were administered with 240 ml of water. Each subject received four treatments within a study according to a 4-sequence randomization schedule. There was a 7-day interval between each treatment period.
For studies HGN007, HGN008, 10850702, and 10850703, blood samples (∼7 ml) for the determination of itraconazole and hydroxyitraconazole concentrations were taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h after the dose. Study HGN008 had additional samples collected at 96 and 120 h. A similar but more extensive pharmacokinetic (PK) sampling schedule for the determination of itraconazole was performed for study MPG009, with additional samples collected at 3.5, 4.5, 5.5, 6.5, 7, 9, 16, 96, and 120 h.
For multidose studies (10850705 and 10850706), 100 mg of SUBA-itraconazole was administered either once or twice daily and compared to 200 mg of Sporanox administered in a similar dosing schedule for 15 days under fed conditions. Blood samples for a determination of itraconazole and hydroxyitraconazole concentrations were taken at −48, −24, 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 h, all relative to the time after dose on day 15.
All subjects who participated in the studies were non-tobacco-using males and nonpregnant nonlactating females who were ≥18 years of age. All subjects were healthy, as determined by the lack of abnormalities in the health assessments performed prior to study participation. Subjects with histories of gastrointestinal disease, malabsorption, and those who received any known CYP3A inhibitors or inducers in the 30 days prior to the study were excluded. All studies were conducted according to the International Conference of Harmonisation (ICH) guidelines for good clinical practice (15), the Declaration of Helsinki on the ethical conduct of medical research (16), and applicable regulatory requirements. Each subject signed and dated a written informed consent before study participation.
Scheduled blood samples were collected in sodium heparin collection tubes and centrifuged within 60 min of collection. The resulting plasma samples were stored frozen at −20°C or below and shipped overnight on dry ice to the analytical facility. For the United Kingdom studies, the analyses of itraconazole and hydroxyitraconazole concentrations were conducted by Covance Laboratory, Inc. (Harrogate, United Kingdom) using a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method after solid-phase extraction of the plasma samples. For the U.S. studies, the analysis was conducted by PPD Laboratory Services (Middleton, WI) using a fully validated high-performance liquid chromatography (HPLC) method with fluorescence detection. The lower limits of quantification of the assays were 0.2 ng/ml and 0.5 ng/ml for the studies performed in the United States and the United Kingdom, respectively.
Population pharmacokinetic analysis. (i) Software.Modeling was performed using a Dell PowerEdge R910 server with 4 by 10 core Xeon 2.26-Ghz processors running Windows Server 2008 R2 Enterprise 64-bit software. Log-transformed plasma itraconazole and hydroxyitraconazole concentrations were used for pharmacokinetic modeling. Model development employed nonlinear mixed-effects modeling using NONMEM (version 7.3; ICON Development Solutions, Ellicott City, MD) (17), ADVAN5 (for modeling itraconazole data only), and ADVAN6 subroutine (for concurrent modeling of itraconazole and hydroxyitraconazole) with the Wings for NONMEM (version 7.3) interface (http://wfn.sourceforge.net) and IFort compiler. First-order conditional estimation method with interaction (FOCE-I) was used to fit models. Processing of the NONMEM output and generation of plots were conducted with the R software version 3.1.1 (18) using the ggplot2, doBy, plyr, reshape2, and scales packages (19–23).
(ii) General modeling strategy.Model development was conducted in a stepwise manner. First, a base model of itraconazole single-dose data was developed, which allowed a focused investigation of food effects on itraconazole absorption, as only the single-dose studies had fed and fasted periods. The base model of single-dose data was then extended to describe the multidose data (and the single-dose studies). Different mechanisms were investigated to describe the accumulation kinetics of itraconazole in the multidose studies. Covariate effects (other than those needed for an accurate structural model) were investigated on the base model of combined single-dose and multidose data. The final covariate model was then extended to describe the concurrent kinetics of itraconazole and hydroxyitraconazole. A simultaneous estimation of the pharmacokinetic parameters of the parent drug and metabolite was also assessed.
Population parameter variability was modeled on pharmacokinetic parameters using a log-normal distribution: (1) where Pi represents the parameter estimate of ith individual, Ppop represents the typical population parameter estimate, and ηi (ETA) is the deviation of Pi from Ppop.
Residual variability was modeled using a combined proportional and additive model of itraconazole and hydroxyitraconazole: (2) where Cij represents the jth observation of the ith individual, Cpred,ij represents the model-predicted Cij, and εij1 and εij2 represent the residual additive and proportional error, respectively, of the jth observation of the ith individual. The combined residual model was adapted for use using the log-transform both sides (LTBS) approach (24); see Appendix S1 in the supplemental material for the code used.
(iii) Base model development of single-dose data.Base model development for single-dose data was conducted following sequential stages in which the best model was selected and carried forward to the next stage. Stage 1 models examined the basic form of the structural model (1, 2, or 3 compartment) and the benefit of a "common variability on bioavailability" approach (FVAR).
Base models included a parameter for SUBA-itraconazole relative bioavailability compared to that of Sporanox (reference value 1), given the known bioavailability differences. First-order oral absorption was assumed for the stage 1 models. The effect of fed status on the absorption parameters was examined in case the effect of fed status on the observed data influenced model selection.
Transit chain absorption models (1- to 6-transit compartments) (25) were examined at stage 2 using the best structural model from stage 1. Stage 3 models examined the effect of fed status on the fixed-effects model parameters of the best model carried from stage 2.
Different methods for representing between-occasion variability (BOV) on PK model parameters were investigated at stage 4. For this purpose, two levels of random effects corresponding to two subject identification codes were defined in the data. The first level was unique by subject (ID) and therefore had common random-effects values for each dose period within a subject. The second level was unique by the dose period (ID2) within a subject and therefore allowed different random-effects values for each treatment period within a subject (i.e., assuming the BOV is equal to between-stage variability [BSV]).
The best model from stage 4 was carried forward to stage 5, which examined: (i) the effects of adding between-study variability on random-effects parameters to further improve the fit of dosing periods and (ii) the hypothesis that the kinetics of itraconazole differed in variability for Sporanox compared to that of SUBA-itraconazole. A scaling factor (ETASCALE) was introduced to allow population parameter variability to differ between the two formulations and was examined systemically on all population PK parameters.
(iv) Base model development of single-dose and multidose data.The best base model of single-dose data was carried forward to develop a model of the combined single-dose and multidose data. Previous studies using noncompartmental approaches revealed nonlinear kinetic behavior for itraconazole and hydroxyitraconazole in a comparison of single-dose versus multidose kinetics or in comparisons of single-dose kinetics of itraconazole across a range of doses (9, 10). A number of mechanisms representing the nonlinearity were examined during the model-building process. The mechanisms investigated included (i) saturable elimination models, (ii) competitive inhibition models, in which an inhibition rate constant was introduced to the saturable elimination model (26) and inhibition was assumed to be a function of either itraconazole or hydroxyitraconazole concentrations, (iii) models invoking time-dependent changes in clearance and/or bioavailability, and (iv) models invoking time- and dose-dependent changes in clearance and/or bioavailability.
(v) Covariate model building.The available covariates in the data were body weight (BW), lean body weight (LBW), total daily dose, formulation (SUBA-itraconazole versus Sporanox), Sporanox origin (United Kingdom versus U.S. origin), study population (United Kingdom versus U.S. population), ethnic group, race, and sex. Potential significant covariates were identified by visualizing plots of the covariates versus the BSV of the parameter estimates. Physiologically plausible covariates were evaluated for statistical significance using a stepwise covariate modeling of forward addition and backward elimination (27). Additionally, it was considered that there may have been an interaction between formulation and dose occasions such that, for example, the first dose occasion of Sporanox differed from all other Sporanox dose occasions. Such interactions were also examined in the model. The statistical criteria for retaining a covariate in the model were a P value of <0.005 during forward addition and a P value of <0.001 for backward elimination.
Continuous covariates were modeled using a power function referenced to the median value of the covariate in the data set (COVmedian) using the equation: (3) where the individual parameter estimate of the jth individual (Pij) with the covariate value COVj was modified from the population value (Ppop) by the value of θ.
Categorical covariates were modeled using a proportional function: (4) where Ppop was the population parameter estimate when the covariate was absent (COV = 0), and θ represented the change in the parameter associated when the categorical covariate was present (COV = 1).
(vi) Metabolite model.Metabolite modeling was performed using a sequential 2-stage approach (28). The final parent drug model was coded with differential equations using the ADVAN6 subroutine in NONMEM.
As the fraction of itraconazole metabolized to hydroxyitraconazole is not known, the metabolic conversion ratio was assumed to be 1 (i.e., all itraconazole cleared from the parent model entered the metabolite model). The clearance and volume parameters for the metabolite model were therefore the apparent values scaled by the unknown metabolic conversion ratio.
The model-building process was analogous to the method used for modeling the parent drug. The most appropriate structural model for hydroxyitraconazole was identified, and then a number of mechanisms were investigated to describe the nonlinearity in the hydroxyitraconazole data. The mechanisms investigated included: (i) similar models used to examine the nonlinearity for the parent drug, (ii) models with enterohepatic recycling for the metabolite, (iii) models with transit compartments for metabolite formation, (iv) mixture models of metabolite clearance, and (v) mixed linear and nonlinear elimination models. Separate residual variability terms were used for itraconazole and hydroxyitraconazole concentrations for the single-dose and multidose data.
The model was fitted to all available itraconazole and hydroxyitraconazole data from the single-dose and multidose studies, with the parameters for itraconazole fixed at the values determined from the final model of the itraconazole data only. Importance sampling was used to assess the precision of the estimated metabolite parameters.
(vii) Model selection and predictive performance.Model selection was guided by the following criteria: (i) plausibility and precision of parameter estimates, (ii) the Akaike information criterion (AIC), (iii) the minimum objective function value (MOFV), and (iv) the inspection of various standard diagnostic plots. The AIC was used to compare nonnested models, in which models with lower AIC were preferred for base model selection. Candidate base models were considered for further analysis if the standard errors of θs and ηs were <30% and 50%, respectively. The likelihood ratio test (LRT) was used to compare nested models with a significance level of a P value of 0.005. Covariates with standard errors (SE) of <51.2% were considered for further analysis.
Visual predictive checks (VPC) (29) were performed to evaluate the predictive performance and adequacy of the models for describing itraconazole and hydroxyitraconazole single-dose and multidose data. For itraconazole and hydroxyitraconazole, the final model was used to simulate 200 versions of the original data set based on the final estimated parameter values of the parent and the metabolite. The observed concentrations and the median and 90% confidence interval of the observed and simulated concentrations were plotted. The VPCs of hydroxyitraconazole were constructed for up to 72 h due to the relatively low number of samples beyond 72 h that resulted in large confidence intervals of the predicted concentrations. VPCs of itraconazole were also constructed for key noncompartmental analysis (NCA) exposure metrics (area under the concentration-time curve from time zero to the last measurable concentration [AUC0–t], maximum concentration in serum [Cmax], and time to Cmax [Tmax]) and were presented as boxplots for comparison. NCA metrics of simulated data below the 2.5th and 97.5th percentiles were not used for summary statistics, as they presented as outliers, and their inclusion was considered to produce summary statistics that were not representative of the model predictions.
Simulations. (i) Food effects.The final model of itraconazole was used to simulate the effect of food on the time course of predicted itraconazole concentrations in fed and fasted states. A crossover design study was simulated 1,000 times using single oral doses of SUBA-itraconazole (58 mg) and Sporanox (100 mg), which would provide equal exposure given the final model estimate of the relative bioavailability. A sample size of 52 subjects was chosen, as this represented the largest number of subjects in the clinical trials included in the present analysis. The median and 90% confidence interval of the predicted itraconazole concentrations were plotted. Itraconazole exposure was assessed by the area under the concentration-time curve from time zero to infinity (AUC0–∞), Cmax, and Tmax. Cmax and Tmax were collated directly from the simulated data. The area under the concentration-time curve from time zero to the last measurable concentration (AUC0–t) was calculated using linear trapezoidal integration of model-predicted concentrations. The area under the concentration-time curve from time zero to infinity (AUC0–∞) was calculated as follows: AUC0–∞ = AUC0–t + Ct/kel, where Ct is the last measurable drug concentration and kel is the elimination rate constant. Calculations were performed in R using an R script.
(ii) Power analysis.The final model of itraconazole was used to perform a power analysis of bioequivalence between the two marketed itraconazole formulations: 50 mg of SUBA-itraconazole compared to a reference 100 mg of Sporanox in fed and fasted states. A crossover design study of 24 and 52 subjects was simulated 1,000 times. Pharmacokinetic exposure parameters (AUC0–∞, AUC0–t, and Cmax) were calculated, as described in "Food effects" above, for the reference (Sporanox) and tested (SUBA-itraconazole) formulations in the fed and fasted states. For each simulated study, the 90% confidence interval (CI) of the geometric mean ratios (obtained from the log-transformed data) of the pharmacokinetic exposure parameters were calculated. Bioequivalence was demonstrated if the 90% confidence interval (CI) of the test/reference ratio for AUC0–∞, AUC0–t, and Cmax for itraconazole fell within the range of 0.8 to 1.25. The percentage of bioequivalence studies was computed for different fed/fasted comparisons of the test versus the reference formulation. The percentage of bioequivalence studies was interpreted as the chance of establishing bioequivalence between the two formulations given the trial design and dose selection used in the trial.
(iii) shiny application.The final model of itraconazole was implemented as a Web application that allows users not familiar with the details of population modeling to perform simulations using the model (30). The application utilizes the shiny package in R programming language (31) and uses validated ADVAN-style analytical solutions (32) of the final itraconazole model.
Study populations and pharmacokinetic data.The U.S. and United Kingdom plasma concentration data used for pharmacokinetic modeling included 15,097 itraconazole plasma samples from 238 subjects and 9,868 hydroxyitraconazole plasma samples from 186 of the subjects. A summary of the subject demographics for the U.S. and United Kingdom studies is presented in Table 2. The observed itraconazole concentrations were 0.2 to 2,850 ng/ml, and the hydroxyitraconazole concentrations were 0.5 to 4,070 ng/ml. Overall, 12.5% and 17.5% of the itraconazole and hydroxyitraconazole data were missing, respectively. The missing data were primarily below the lower limit of quantitation (LLOQ) and occurred primarily at the beginning or the end of the observation period. Models accounting for LLOQ-censored data using the YLO and M3 methods (33) were investigated and were found to be characterized by unreliable minimization and covariance step status. Samples below the limit of quantitation (BLQ) were thus excluded a priori from the data set (M1 method). No impact on parameter estimates was demonstrated, as there were sufficient data points in the elimination phase of itraconazole, and the hydroxyitraconazole data were unaffected by censoring (figures not shown). This was subsequently confirmed by the final model.
Base model of single-dose studies.The best structural model identified at stage 1 was a two-compartment first-order absorption model including common variability on bioavailability coding and the effect of fed status on absorption parameters (bioavailability and absorption rate constant). The model allowed the magnitude of the residual error to differ with fed status. The transit compartment models at stage 2 performed substantially better than the first-order absorption models. The 4-transit compartment model was the best model to describe oral absorption and was associated with an AIC reduction of 1,295 units compared to the use of first-order absorption with a lag time.
The stage 3 models examined the effect of fed status on fixed-effects parameters of the 4-transit absorption model selected at stage 2. The best model that passed the selection criteria incorporated the effect of fed status on the transit-compartment rate constant (KTR) and bioavailability (F). The bioavailability model lowered the AIC by 4,381 units compared to the reference model (the best model at stage 2) and was carried forward to the next stage.
The models at stage 4 differed in the level of random effects by subject identification (ID) (ID-class models) or by dose period (ID2-class models). Initially, the best model at stage 3 was extended by the addition of BOV on random-effects parameters using subject ID as the level of random effects. Incorporating BOV into the ID-class models resulted in a large drop in the AIC (e.g., adding BOV on F and KTR dropped the AIC >10,800 units), which suggests that the BOV was substantially larger than the BSV. However, most of ID-class models terminated unsuccessfully, and all failed to pass a covariance step (either aborted or none), taken as an indication of overparameterization. In addition, all models were characterized by low eta P values of random effects, which indicated a biased distribution of the empirical base estimate etas (EBE-etas). To allow more freedom in finding a description of the dose periods within a subject, it was assumed that an ID-class model with BOV on all parameters was equivalent to an ID2-class model when BOV is substantially larger than BSV. Therefore, the best ID2-class model was carried forward to stage 5, this being the best model from stage 3.
Adding between-study variability on random-effects parameters did not improve the fit of the model any further (ΔOFV, 0). Incorporating an ETASCALE parameter of the formulation on the population variability in bioavailability lowered the AIC by 15 units, and all model parameters were estimated precisely (percent standard error [%SE], <30%). Adding a scale parameter on the other population variability parameters resulted either in imprecise parameter estimates or terminated runs. Therefore, the best model at stage 5 incorporated an ETASCALE parameter of the formulation on the population variability in F and was declared as the final base model of single-dose data.
The base model supported BSV on the apparent central clearance (CL/F), apparent central volume of distribution (V1/F), and KTR. All base model parameters were estimated precisely (%SE, <30%), and diagnostic plots were able to describe the data very well, with no systematic bias. The estimated population pharmacokinetic parameters of the best base model of single-dose data and representative diagnostic plots of the model are provided in Table S1 and Fig. S1 in the supplemental material.
Base model of single-dose and multidose data.Initial fitting of the combined single- and multidose data using the best single-dose model showed that the multidose concentrations were substantially underestimated (data not shown). Nonlinear elimination kinetics can cause changes in both clearance (lower clearance with higher doses due to systemic saturation of clearance) and bioavailability (higher bioavailability for higher doses due to reduced first-pass effect). Among the different methods examined to investigate the nonlinearity of the multidose data, itraconazole nonlinear kinetics was best described by the total effective daily dose- and time-dependent changes in clearance and bioavailability for multidose studies compared to those of the single-dose studies.
The total effective daily dose- and time-dependent changes in clearance allowed the clearance of the multidose studies to decrease exponentially compared to that of the single-dose studies, depending on the total effective daily dose of itraconazole (equation 5). The effective daily dose (EDD) was the total daily dose of itraconazole corrected for the relative bioavailability difference between the two formulations. As per Lehr et al. (34), itraconazole approaches steady state after ∼7 days of continuous administration. The rise to steady-state concentration with time (i.e., the decrease in clearance with time) was described exponentially by equation 6. The rate constant (kss) for the exponential decrease in clearance with time was fixed to 0.5 day−1, as no data were available during the approach to steady state. (5) where DDCLss represents the effect of effective daily dose on clearance, DDmax represents the maximum effect of EDD on clearance, and DDK was a rate constant for EDD on clearance. (6) where DDCL represents the change in clearance with time, kss represents the rate constant for the rise to steady-state concentration, and DAY is the time in days since the first dose.
Similarly, the time course of the change in bioavailability for the multidose studies during the accumulation phase was described by equation 7. (7) where DDF represents the change in bioavailability with time (days) and DDFss represents the effect of effective daily dose on bioavailability at steady state.
Introducing dose- and time-dependent changes on clearance and bioavailability for the multidose studies resulted in drops in the AIC of 661 units and 280 units, respectively, compared to the reference model without introducing these effects.
The parameters for the best base model of single-dose and multidose data were estimated precisely (%SE, <30%), and diagnostic plots were compatible with a well-formed population model (data not shown). This model was declared the base model for testing the addition of covariates.
Covariate models.The following potential significant covariate relationships (in addition to those used in building of structural model) were assessed during covariate model building: weight (WT) on CL/F and central volume of distribution of itraconazole (V2)/F, LBW on CL/F and V2/F, total daily dose on CL/F and KTR, weight on V2/F and KTR, formulation and ethnic group on KTR, an interaction between dose occasions for Sporanox on KTR, and Sporanox origin and study population on all pharmacokinetic model parameters.
Significant univariate models identified in the first forward addition step had an effect of study population on KTR (ΔOFV, −5,597.7), CL/F (ΔOFV, −45.7), and an effect of WT on CL/F (ΔOFV, −9.8) compared to the base model. The inclusion of other covariates failed to meet the selection criteria. The best univariate model with an effect of study population on KTR was investigated in combination with the other significant covariates. Adding the weight covariate in the second forward addition step resulted in an imprecise parameter estimate (%SE, 80.5%) and therefore, was not considered further. The best model in the second forward addition step had an effect of study population on the KTR and CL/F of itraconazole and was retained significant in the backward deletion step.
The final estimated population pharmacokinetic parameters for all fixed and random effects in the final itraconazole model are presented in Table 3, and diagnostic plots are given in Fig. 1. The NONMEM control stream for the final itraconazole model is provided in Appendix S1 in the supplemental material. As shown in Table 3, all model parameters were estimated precisely and had acceptable standard errors (%SE, <30%). The standard goodness-of-fits plots in Fig. 1 show that the data were symmetrically distributed around the unit slope lines of with no major systematic bias. The observed versus individual predicted concentrations were tightly clustered around the identity line across the range of measured values, indicating that these data were adequately described by the model. Similar diagnostic plots were obtained when the data were conditioned by formulation and fed status (see Fig. S2 and S3 in the supplemental material).
SUBA-itraconazole had a relative bioavailability of 173% compared to that of Sporanox, and the bioavailability was 21.3% less variable (Table 3). The fed status influenced the kinetics of itraconazole via two mechanisms: (i) a decrease in the relative bioavailability to 73.1% of the fasted state, and (ii) a decrease in transit absorption rate constant (KTR) to 41.7% of the fasted state, which corresponds to an increase in the mean transit time (MTT) of the drug from a population value of 1.95 h in the fasted state to 4.68 h in the fed state. The apparent central clearance (CL/F) and KTR for subjects from the United Kingdom studies were 83.4% and 133.8%, respectively, compared to those for subjects from the U.S. studies (Table 3).
Metabolite model.Hydroxyitraconazole data were best described by a one-compartment model with mixed linear (first-order) and nonlinear (Michaelis-Menten) elimination for the single-dose hydroxyitraconazole data and a time-dependent linear clearance for hydroxyitraconazole multidose data. The final parent-metabolite model is presented in Fig. 2.
The time-dependent clearance allowed the metabolite clearance of multidose studies to differ with passage of time from the single-dose studies (reference value = 1) by a factor that might represent changes of clearance due to enzyme inhibition (or induction). Equation 8 shows the change in clearance for the multidose hydroxyitraconazole data: (8) where TIMECL represents the change in clearance for multidose studies from the single-dose studies. CLm, CLpop, and η represent individual metabolite clearance, typical metabolite clearance, and between-subject variability, respectively.
The addition of time-dependent clearance with linear elimination for the multidose studies adequately described hydroxyitraconazole concentrations and was associated with an AIC reduction of 2,150 units compared to a reference one-compartment model. Despite providing a good description of the multiple-dose data, the model was associated with biased predictions for the single-dose data. The addition of mixed linear (first-order) and nonlinear (Michaelis-Menten) elimination for the single-dose data resulted in a further reduction in the AIC by 2,353 units and was the best model to adequately describe hydroxyitraconazole concentrations in the single-dose studies. The final parameter estimates for the metabolite component of the model are presented in Table 4, and key diagnostic plots are given in Fig. 3. The NONMEM control stream of the final metabolite model is provided in Appendix S2 in the supplemental material. All parameters were precisely estimated (%SE, <38%). The conditional weighted residuals-versus-time plot showed that most of the data points were symmetrically distributed within −6 and +6 units, as appears in Fig. 3. The few data points outside this range were examined and were from 4 different subjects (3 subjects from the multidose studies and one subject from a single-dose study). However, there was no bias observed, and none of these points were justifiably deleted from the data set. Only study 8 had metabolite data after 72 h, and most of them (∼86%) were missing.
Visual predictive checks.The visual predictive check (VPC) plots for itraconazole and hydroxyitraconazole are presented in Fig. 4, 5, and 6. Itraconazole VPCs for key noncompartmental analysis (NCA) exposure metrics (AUC0–t, Cmax, and Tmax) are provided in Fig. S4 to S6 in the supplemental material.
The VPC of itraconazole showed that the final model has good predictive performance for single-dose and multidose data (Fig. 4) and for single-dose data conditioned on formulation and fed status (Fig. 5). The time course of the median and 5th and 95th percentiles were similar for the observed and simulated concentrations. The model also showed good predictive performance for itraconazole when the plots were conditioned on study, dose, formulation, and fed status (figures not shown). The itraconazole exposure metrics VPCs showed an acceptable agreement between the model predictions and observed data for AUC, Cmax, and Tmax.
The VPCs of hydroxyitraconazole in Fig. 6 demonstrated an acceptable agreement between the observed and simulated concentrations for multidose data; however, there was a deficiency in the model in predicting the early time course of hydroxyitraconazole concentrations in single-dose studies.
Simulations. (i) Food effects.The effect of fed status on model-predicted itraconazole concentrations using single-dose studies as an example is shown in Fig. 7, and the effect on model-predicted NCA metrics is summarized in Table 5. The population effect of food was to decrease the AUC0–∞ of itraconazole to 78 to 81% of that in the fasted state, to decrease the Cmax to 62 to 65% of that in the fasted state, and to increase Tmax to 177 to 184% of that in the fasted state. The effect of fed status on itraconazole exposure was independent of formulation, other than the lower variability in exposure for SUBA-itraconazole due to the less variable relative bioavailability.
(ii) Power analysis.While the final model suggested that a 58-mg (95% CI, 52.6 to 64.0 mg) SUBA-itraconazole dose was expected to have the same exposure by AUC as 100 mg of Sporanox, the predicted performance of the marketed 50-mg tablet in bioequivalence studies is of interest, as it provides some insight into the difficulties of establishing bioequivalence for a drug with varied kinetics and a pronounced food effect. The percentages of bioequivalence studies for 50 mg of SUBA-itraconazole (test) compared to a reference 100 mg of Sporanox (reference) in the fed and fasted states are shown in Tables 6 and 7 for studies with 24 and 52 subjects, respectively. The comparison with the highest overall power was test/fasted versus reference/fasted, with a study size of 52 subjects (average power, 84.8% across all 3 exposure metrics), with the next highest power being test/fed versus reference/fed with a study size of 52 subjects (average power, 74.5% across all 3 exposure metrics). The reduction in study power when using 24 subjects rather than 52 was relatively small (e.g., from 84.8% to 74.1% average for test/fasted versus reference/fasted); however, as the power to find bioequivalence for all three exposure metrics concurrently is likely to be lower than the individual values (i.e., the product of the three probabilities if they are independent), the relatively small increase in power between a study with 52 rather than 24 subjects may be important in cases in which the criterion is to test bioequivalence for all three exposure metrics. Comparisons of test/fed versus reference/fasted or vice versa were characterized by low power for finding bioequivalence by Cmax. However, comparisons of both fed and fasted 50-mg SUBA-itraconazole doses with a fed 100-mg Sporanox dose were adequately powered for finding bioequivalence by AUC, in keeping with the labels for SUBA-itraconazole and Sporanox. It is notable that comparisons of the fed and fasted states for the same formulation (for both AUC and Cmax) generally had lower power than the comparisons of formulation, with much lower power for finding bioequivalence by Cmax (<10.6%). This reinforces the important role that fed status (and presumably gastric pH) has in dictating itraconazole exposure for these formulations.
Shiny application.The shiny application for the final itraconazole model can be accessed at https://acp-unisa.shinyapps.io/Itraconazole_PopPK_Model/. The application allows one to simulate once- or twice-daily dosing of Sporanox or of SUBA-itraconazole in the fed or fasted state and for various doses and treatment durations. Users are required to click the "start simulation" button every time they change the slider input(s) or widget value(s). Simulated data using the selected dosing regimen can be downloaded as a *.csv file. The ADVAN-style analytical solution of the final model and the R codes for the shiny apps are provided in Appendix S3 in the supplemental material.
A population pharmacokinetic model was developed for itraconazole and hydroxyitraconazole using extensive single-dose and multidose oral data collated from seven clinical trials to compare SUBA-itraconazole with the innovator product Sporanox. The analysis was performed with a particular emphasis on capturing the differences between the two formulations and quantifying the effects of food on itraconazole absorption kinetics. To our knowledge, this paper presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature and is the first paper to investigate the effects of food on the absorption of itraconazole in healthy subjects using the population approach.
The final model of itraconazole consists of a 2-compartment model with oral absorption described by 4-transit compartments. The final model used a common variability parameter on bioavailability, which allowed parameters affected by bioavailability to share a source of variability. This approach was considered to stabilize the model by accounting for an important source of correlation between affected parameters and reducing unexplained between-subject variability in the parameters (24).
Population pharmacokinetic models of itraconazole kinetics in the literature to date have used linear elimination kinetics (35–40). Linear itraconazole kinetics was also found for the model of single-dose data developed in this analysis, but this model underpredicted multidose concentrations, suggesting a deviation from the assumption of linearity outside the single-dose setting. Nonlinear kinetics of itraconazole and hydroxyitraconazole have been reported when NCA methods were used to compare single- versus multiple-dose administration or single-dose administration across a range of doses (9, 10).
Various models for an apparent decrease in clearance, an increase in bioavailability, or both were investigated to describe the accumulation kinetics of itraconazole for the multidose data. Models invoking saturable elimination or time-dependent changes in clearance and/or bioavailability were not adequate in describing itraconazole accumulation and were characterized by goodness-of-fits plots with population-predicted values substantially below the observed values for the multidose data. Lehr et al. (34) also found that saturable elimination alone was not sufficient to describe the accumulation kinetics of itraconazole when it was used as an inhibitor in a drug-drug interaction study. However, Lehr et al. (34) was able to identify a competitive inhibition model based on assumed hydroxyitraconazole concentrations and sparse itraconazole concentrations collected over approximately 1 week. For the data used in the current analysis, there were limited data to inform the time course of itraconazole/hydroxyitraconazole accumulation. All competitive inhibition models invoking an inhibitory effect of the parent drug or the metabolite on the clearance of the parent drug were characterized by unreliable minimization and were not able to adequately describe itraconazole accumulation. However, a semiempirical description of itraconazole nonlinear kinetics was achieved in the final model by allowing the clearance and bioavailability of the multidose studies to change with time based on the evidence that the rise to steady state was as described by Lehr et al. (34), in which itraconazole approaches steady state after ∼7 days of continuous administration. The equations describing the change in clearance and bioavailability (equations 6 and 7) allowed predictions of itraconazole concentrations on days other than day 15. Both equations assumed that the reference values for clearance and bioavailability were as for the single-dose studies.
The kinetics of oral itraconazole was characterized by high variability (% coefficient of variation [CV]) between dose occasions in clearance (22.1%), central volume of distribution (30.7%), transit absorption rate constant (44.8%), and bioavailability (56.4%). The high variability in itraconazole kinetics resulted in a high variability in exposure for a given dose. The effect of study population on KTR and CL/F was the only covariate (other than the effect of fed status and formulation) that was statistically significant in the final covariate analysis. Other subject-related covariates available in the data, including body size (weight), body shape (LBW), and race, were not able to explain the high variability in itraconazole kinetics. Therefore, it is most likely that this variability is related to local conditions in the gastrointestinal tract (GI), such as pH and transit time, which may affect dissolution and absorption of the drug for which subject-specific and occasion-specific data were not available. Also, there is considerable variability in CYP3A4 activity between subjects (41), which may be another major source of intersubject variability in itraconazole pharmacokinetics via its impact on clearance and first-pass metabolism.
The main difference between the SUBA-itraconazole and Sporanox formulations of itraconazole was the relative bioavailability. SUBA-itraconazole had a relative bioavailability of 173% (95% CI, 156 to 190%) compared to that of Sporanox. Thus, a 58-mg (95% CI, 52.6 to 64 mg) dose of SUBA-itraconazole would provide equivalent exposure to the marketed 100-mg Sporanox formulation. The model also supported the hypothesis that SUBA-itraconazole provides more consistent itraconazole exposure than Sporanox, as the variability in the relative bioavailability of SUBA-itraconazole was 78.7% of that of Sporanox. The solid dispersion of itraconazole in the pH-dependent polymeric matrix of SUBA-itraconazole enhances drug dissolution and targets drug release in the proximal small intestine, which is the primary site of itraconazole absorption. On the other hand, itraconazole dissolution in the Sporanox formulation is limited to the gastric environment, resulting in a supersaturated solution of the drug in the stomach. Various studies have demonstrated improved oral bioavailability of poorly water-soluble drugs via targeting of drug supersaturation to the intestinal lumen, rather than the stomach, by the use of pH-dependent carrier polymers (42–44). In one study, Kohri et al. (42) evaluated the use of a solid dispersion system with a pH-dependent polymeric carrier (hypromellose/hypromellose phthalate) to improve oral bioavailability of albendazole, a poorly water-soluble weakly basic drug with a pH solubility profile similar to that of itraconazole. In vitro dissolution tests, using a pH shift method, confirmed that the polymer maintained albendazole supersaturation following a pH shift from pH 1.2 to 6.5. In vivo studies conducted on rabbits with elevated gastric pH showed 3.2-fold improvement in the bioavailability of albendazole compared to that with a crystalline drug. The improvement in the bioavailability was attributed to the targeted supersaturation of the drug to the small intestine, which is a result of the pH-dependent release of the drug from the solid dispersion formulation. In another in vivo study conducted in rats, Miller et al. (44) demonstrated that the addition of Carbopol974P into the Eudragit L-based solid dispersion system of itraconazole exhibited a 5-fold improvement in the oral absorption compared to that of the reference formulation (44). The increase in the bioavailability was suggested to be attributed to the targeted intestinal delivery and prolonged supersaturation of itraconazole in the small intestine.
In the present analysis, food decreased the rate and extent of drug absorption, mediated by a decrease in bioavailability and a lower absorption rate compared to those of the fasted state. The observed food effects on itraconazole kinetics were irrespective of the formulation. Simulated food effects for Sporanox in this analysis are in contrast to the product label for Sporanox, which states that Sporanox should be given with food to enhance absorption (5).
The observed food effects on itraconazole are in contrast to the general trend of BCS class II drugs, which are more likely to show a positive food effect on absorption, mainly due to micellar solubilization. However, it is recognized that BCS class II drugs should not be grouped together but rather subdivided into weak acids and weak bases, with low or high pKa, and lipophilic compounds (45). Each of these may respond differently to food effects. In fact, the majority of BCS class II drugs are weak acids/bases with high pKa and generally show a positive food effect on absorption (45). However, BCS class II drugs with low pKa (e.g., itraconazole and ketoconazole) may precipitate in the stomach or upper small intestine, partially due to the net increase of the gastrointestinal pH after the ingestion of meals; therefore, they may show a negative food effect. Significant luminal intestinal precipitation was observed previously for ketoconazole (a poorly water-soluble weakly dibasic drug, pKa 2.95 and 6.51) administered as an oral solution (pH 2.7) to 12 healthy subjects at both low- and high-dose levels (46). Precipitation of the dissolved drug was also suggested by Carver et al. (47), further to the reduced dissolution, as a potential mechanism for the reduced bioavailability of indinavir (a poorly water-soluble weakly basic BCS class II drug; pKa, 3.7 and 5.9) when administered to HIV-infected patients after a high-protein meal (47).
Prandial status has different effects on the absorption and bioavailability of marketed triazole antifungals. Voriconazole (pKa, 1.7) administered with a high-fat breakfast resulted in a significant decrease in both the AUC0–t and Cmax by 35% and 22%, respectively (48). On the other hand, a high-fat meal significantly enhanced the rate and extent of posaconazole absorption (pKa, 3.6 and 4.6) administered as an oral suspension in healthy subjects (49, 50). However, unlike itraconazole, posaconazole is mainly excreted unchanged in the feces, so the effect of food on intestinal and/or hepatic metabolism is expected to be minimal (51).
Reports in the literature of food effects on itraconazole absorption for Sporanox, using noncompartmental analysis, show substantial interstudy variability in the reported AUC values in the fed and fasted states (e.g., see references 11–14). Yun et al. (11) suggest that the variability in fasting AUC across studies might be related to the volume of fluid administered with the dose. In addition, the dissolution of itraconazole is a function of GI pH, which is highly varied between and within subjects, even under fasted conditions (52, 53). The variability in fed AUC also appears to be a function of the acid content and fat content of the meal (11, 14). The standardized high-fat high-calorie breakfast in the present analysis behaved like the rice meal of Yun et al. (11), with lower overall simulated AUC values in the fed state than those in the fasted state (Fig. 7 and Table 5).
Various models have been investigated for modeling hydroxyitraconazole single-dose and multidose data sets, including similar models investigated for modeling the parent drug. Neither linear nor saturable elimination kinetics alone with/without time-dependent nonlinear clearance were adequate in describing the elimination kinetics of hydroxyitraconazole. Enterohepatic recycling, transit compartment models for metabolite formation, and competitive inhibition models, invoking an inhibitory effect of the parent drug and/or the metabolite (which included simultaneous fitting of parent and metabolite), on the clearance of the metabolite were characterized by unreliable minimization and were not considered further. Similarly, using mixture models of metabolite clearance in an attempt to account for the heterogeneity in CYP3A4 enzyme activity, assuming that hydroxyitraconazole underwent further metabolism by CYP3A4 enzymes, was not successful. The best hydroxyitraconazole model used mixed linear and nonlinear elimination for single-dose data and allowed a separate change in clearance for multidose studies with the passage of time by a factor that might represent changes in clearance due to enzyme inhibition (or induction). However, only the final magnitude of this change at day 15 (as opposed to its magnitude and time course) could be estimated from the available data. The final hydroxyitraconazole model gave an adequate description for multidose data; however, it underpredicted the early time course of hydroxyitraconazole in the single-dose data (Fig. 6). Nevertheless, this was the best model that can be attained from the available data, and it may indicate that the formation of the metabolite may be more complicated than can be represented using simple compartmental models.
One application of the presented model is to perform a prestudy power analysis, which is an important aspect of clinical trial design of bioequivalence studies. The presented model can be used, through simulations, to assist in sample size and dose selection to be used in the trial. However, one insight from the present analysis is that the conclusions drawn from single-dose bioequivalence studies may not fully reflect the behavior of itraconazole in clinical use due to the combined effects of low study power/high variability in kinetics, nonlinearity in accumulation kinetics, and the inherent between-subject and between-study variability in itraconazole absorption, presumably due to variability in the effects of food and gastric pH.
One limitation of the present analysis is that trials were conducted on healthy subjects, with the majority having a body mass index (BMI) in the normal range, but not on actual patients with invasive fungal diseases who may have different absorption kinetics for the drug. Therefore, it is unproven at this time whether the presented model can be used for a clinical evaluation of therapeutic efficacy of the drug in patients with fungal diseases.
The model presented here is acceptable for the intended purposes of quantitating relative bioavailability, food effects, and power analysis in healthy subjects. However, we postulate that a more detailed mechanistic understanding of the influence of pH, food, and first-pass processes on the oral absorption of itraconazole will require using semiphysiological models of first-pass metabolite production (54) and the linking of in vitro dissolution profiles with in vivo kinetics (55). We are currently investigating such models.
All the pharmacokinetic studies used in the analysis were sponsored by Mayne Pharma International.
S.M. and D.H are employees at Mayne Pharma International. R.N.U. has acted as a paid consultant for Mayne Pharma International. The Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy. A.Y.A. is a Ph.D. student receiving an Endeavor Scholarship funded by the Department of Education and Training of the Australian Government (scholarship ID 4088).
- Received 23 April 2015.
- Returned for modification 25 May 2015.
- Accepted 28 June 2015.
- Accepted manuscript posted online 6 July 2015.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00973-15.
- Copyright © 2015, American Society for Microbiology. All Rights Reserved.


text:
10 Alarming Symptoms Of High BP You Shouldn't Ignore: Effective Tips To Lower Your BP Quickly
High blood pressure or Hypertension is often called the "silent killer". If left untreated, high blood pressure can lead to major cardiovascular diseases, like a heart attack, panic attack or a stroke. No doubt, heart disease is one of the leading causes of death all over the world. People who have high blood pressure are at a higher risk of heart diseases than others. Your arteries carry the blood from your heart throughout your body. Blood pressure is the measure of how hard your blood is pushing against the arterial wall. Although a certain amount of pressure is needed to carry blood through your body, if that pressure is too high, you have high blood pressure, or hypertension. High blood pressure can have daunting effects on your health like enlarged heart, kidney damage, eye damage or hardening of the arteries. The only way to know if your blood pressure is high is through regular checkups.
Some common symptoms of high blood pressure are:
Chest pain
Facial flushing
Shortness of breath
Blurred vision
Blood in urine
Abnormal heart beat
Here's how you can avoid high blood pressure:
1. Stress: Any sort of psychological stress; whether it is financial, work-related or relationship should be avoided. Stress can lead to numerous poor health outcomes, high blood pressure or hypertension being one of them.
2. Diabetes: People who have high blood sugar are at a higher risk of hypertension. It is very important that this is detected, and carefully managed. People who are diabetic need to change their lifestyle by healthy eating habits, avoiding processed food, limiting alcohol, proper medication, adequate rest, reduce salt intake and regular physical exercise.
3. Obesity: Blood pressure often increases when weight increases. It is extremely essential to maintain a normal Body Mass Index (BMI) which is 20-25. Having a BMI greater than 25 increases your risk of high blood pressure. Weight loss can significantly reduce your blood pressure. Therefore, it is extremely important for us to maintain a healthy body weight.
4. Inactivity: We all know that physical activity is essential for the overall health. Regular physical exercise is important as your heart is also a muscle. Like all the other muscles in your body, it also needs to be exercised regularly in order to keep it strong and healthy. This means it should pump the blood efficiently round the body and your blood pressure is naturally lowered.
5. Healthy diet: A healthy diet is extremely important in all the stages of life. You should include fresh fruits and dark green leafy vegetables, dairy products, proteins, fibre rich foods, low-fat dairy products, whole grains and foods rich in potassium in your diet. Eating right is the key to healthy living.
Foods to eat if you have high blood pressure:
Healthy nuts
Seeds like flax seeds and chia seeds
Foods to avoid if you have high blood pressure:
Packaged foods
Processed meat
Frozen food
Common Causes of Neck and Shoulder Pain
If you have a 9 to 5 job that requires you to sit in front of a computer, chances are you have been bugged by neck and shoulder pain for many times already.The discomfort you feel may range anywhere from mild to severe. Moving the affected area may trigger the pain or cause it to worsen.
Non-steroidal anti-inflammatory drugs or NSAIDs are the most commonly prescribed drugs to those who are suffering from neck and shoulder pain. The problem with the intake of these medications is they yield unfavorable side effects most especially when taken for a long period of time. The application of liniment may also be done, although the topically used product may cause skin irritation in some.
It's for these reasons why considering a few home remedies for dealing with neck and shoulder pain is a good idea. Some of them include:
• Alternating hot and cold compress – Doing this for about 20 minutes several times a day can help get rid of the pain and inflammation in the affected areas. If you have the problem, you may also take a shower using cold and water alternately to attain relief.
• Mobilizing the neck and shoulder – Immobilizing the painful area for a long time may only do more harm than good. That's why after about 48 hours or when the pain and inflammation have subsided a bit, gently mobilizing the neck and shoulder can help in restoring function as well as flexibility and strength of the muscles in the area.
Neck and shoulder pain can be due to several different reasons. When having the problem, it's very important to pinpoint the cause so that it may be managed appropriately. Here are the common causes:
• Poor posture. Naturally, it's very likely for you to suffer from neck and shoulder pain if your posture is not top-notch. No matter if you are standing up, sitting down or lying, proper posture is important in order to have the problem avoided.
• Overuse of the muscles and joints of the neck and shoulders. Repeated movements of the neck and shoulder can cause pain in these areas as the muscles get fatigued and the joints are given more work than they could normally handle.
• A pinched neck or shoulder nerve. When there's compression of the nerve in the neck or shoulder or too much pressure is applied to it, a condition called pinched nerve may occur. The pain felt also usually runs down on one side of your arm.
• Frozen neck or shoulder. A frozen neck or shoulder usually stems from the lack of movement due to pain and inflammation brought about by an injury. As more and more movement is introduced, the problem gradually goes away.
• Swelling of a tendon in the neck or shoulder area. Medically known as tendonitis, the swelling of a tendon (a band that attaches a muscle to a bone) can cause pain in the neck and shoulder, also causing the said areas to be frozen.
• Inflammation of the bursa. This condition which is also referred to as bursitis is brought about by overuse, trauma, gout, arthritis and infection, thus causing the bursa (sac surrounding the shoulder joint) to get inflamed.
• Whiplash and osteoarthritis. Both whiplash (injury to the neck due to forceful and rapid back-and-forth movement of the neck joint) and osteoarthritis (degeneration of the cartilage of a joint) may also result in neck and shoulder pain.
• Inflammation of the lymph nodes found in the neck. There are instances when pain in the neck and shoulders is brought about by an infection, causing the lymph nodes in the neck to get inflamed and tender.
How to Remove Uric Acid Crystallization in Joints (Gout and Joint pain)
Gout and pain in the joints are known conditions that affect a lot people. Some go for supplements and over-the-counter medicine for relief.
What many do not know is that many healthy remedies are available to help in dealing with these conditions. Besides being convenient and effective, natural ways also offer added health benefits to the body.
What you will read next is a great and healthy way to remove uric acid crystallization in joints.
Cucumber is one produce you would always want to the grocery for. Making a juice out of it is great at bringing down the temperature of the body. Besides its being a an effective alkalizing agent, it also works well In the removal of the uric acid that has been crystalized in the joints which usually happens in the case of gout.
When drinking this juice, a slight pain might be felt. This is good because this is a sign that healing is taking place. This happens when the old toxins that will be removed are being stirred.
You might want to add want to add ginger and celery. They work well in the reduction of inflammation when the body undergoes a cleansing process.
To prepare this mix you will need the following:
• 2 ribs of celery
• 1 average sized cucumber
• A slice of lemon
• 1 inch young ginger root
Make sure that you have prepared all the necessary ingredients. Clean them well. You may use some vegetable wash or wash them thoroughly.
First, make small cucumber pieces. Slice them in such a way that they will fit into your juicer. Know your juicer's capacity. Then check the rib of the celery. Make sure that you got rid of the dirt that has accumulated on it. After that, take the lemon and cut it into half. This is all you need. Put the other half in the fridge. Lastly, get the ginger root and carve it out.
Enjoy the drink and deal with the crystalized uric acid. Drink as often as needed.
Endogamy may up infertility risk in Indian men
A team of researchers have identified that deletions of the Y chromosomes, responsible for the production of sperms, can cause infertility in Indian men.
The study, published in the journal, 'Scientific Reports', illustrates how the ethnicity, endogamy and long-time geographical isolation of Indian populations might have played a major role in the high frequencies of deletion events.
According to the researchers, including K Thangaraj from Centre for Cellular and Molecular Biology, deletions in the A Zoospermia Factor (AZF) regions on the human Y chromosome are reported as one of the most common causes of severe testiculopathy and spermatogenic defects leading to male infertility.
For the study, the researchers screened blood samples of 973 infertile men, consisting of 771 azoospermia (complete absence of sperm), 105 oligozoospermia (low sperm count) and 97 oligoteratozoospermia (low sperm count with abnormal shape and size) patients.
The deletion screening was carried out using AZF-specific markers.
The experiments were carried in accordance with the relevant guidelines and regulations approved for research on human samples.
The study revealed deletion events in a total of 29.4 per cent of infertile Indian men. Of these, non-allelic homologous recombination events accounted for 25.8 per cent.
Indian populations are unique in their origin and have been practicing endogamy for the last two thousand years, and therefore it is important to add a study of the frequencies of AZF deletions on the Y chromosome and their association with fertility in Indian idiopathic infertile men to similar studies from other parts of the world, the researchers said.

subset: commoncrawl


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Bee-shaped device takes the sting out of injections
Beeline Reader
We're constantly looking for innovative ways to improve the Springwise experience, and so we're now introducing BeeLine Reader, a new technology that helps you read more quickly and efficiently. To learn more about BeeLine Reader, an award-winning startup funded by Intel Capital, see BeeLineReader.com.
Shots aren't an enjoyable thing to experience, and unhappy or tense patients make the job more difficult for the doctor. Designed to distract them from the pain of injections, Buzzy is a bee-shaped device that uses ice and vibrations to calm both kids and adults receiving shots. Created by pediatrician and pain researcher Dr Amy Baxter, the Buzzy can be strapped around or simply placed near to the location of the jab. The device contains a vibrating motor in the body of the bee, while its wings are made of ice packs. It works because the combination of cold temperature…
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Avengers: Endgame
The most blockbuster of all the blockbusters.
The most blockbuster of all the blockbusters.
The subject is so interesting, and the music played by these people is so gorgeous.
Roger Ebert on James Ivory's "Howards End".
"The Ballad of Narayama" is a Japanese film of great beauty and elegant artifice, telling a story of startling cruelty. What a space it opens…
Emerging female filmmakers present their short films directed in the (Chicago Housing Authority) CHA/DePaul University spring Documentary Film Premiere scheduled for Sunday, April 28th. They…
An article celebrating the historic Chicago mayoral runoff between two African-American women, Toni Preckwinkle and Lori Lightfoot.
Potentially another "Dog Day Afternoon." Too bad about the execution.
A video essay that celebrates Lilly and Lana Wachowki's 2015 film, Jupiter Ascending.
A Far Flung Correspondent looks at Cristian Mungiu's award-winning film.
American Splendor is an under-appreciated gem which deserves more attention.
A review of CBS' eight-episode series The Red Line, which premieres on Sunday, April 28.
The stars of Hulu's Ramy talk about religion, representation, and translating stories from stand-up to a television format.
Gene Siskel proposed an acid test for a movie: Is this film as good as a documentary of the same people having lunch? At last, with "Stolen Summer," we get a chance to decide for ourselves. The making of the film has been documented in the HBO series "Project Greenlight," where we saw the actors and filmmakers having lunch, contract disputes, story conferences, personal vendettas, location emergencies and even glimpses of hope.
Movies are collisions between egos and compromises. With some there are no survivors. "Stolen Summer" is a delightful surprise because despite all the backstage drama, this is a movie that tells stories that work--is charming, is moving, is funny and looks professional. That last point is crucial, because as everyone knows, director Pete Jones and his screenplay were chosen in a contest sponsored by Miramax and actors Ben Affleck and Matt Damon. Miramax gave them a break with their screenplay "Good Will Hunting," and they wanted to return the favor.
"Stolen Summer" takes place on the North Side of Chicago in the summer of 1976, when an earnest second-grader named Pete O'Malley (Adi Stein) listens in Catholic school and believes every word about working his way into heaven. Seeking advice from a slightly older brother about how to guarantee his passage to paradise, Pete is startled to learn that the Jews are not seeking to be saved through Jesus. So Pete sets up a free lemonade stand in front of the local synagogue, hoping to convert some Jews and pay for his passage.
There is already a link between Pete's family and that of Rabbi Jacobson (Kevin Pollak). Pete's dad, Joe (Aidan Quinn), is a fireman who dashed into a burning home and rescued the Jacobson's young son Danny (Mike Weinberg), who is about Pete's age. Pete has already met the rabbi and now becomes best friends with his son, although Danny is not much interested in the theology involved, he joins Pete's "quest" to get them both into the Roman Catholic version of heaven. Is Pete's obsession with church rules and heaven plausible for a second-grader? Having been there, done that, I can state that this was not an unknown stage for Catholic school kids to go through, and that I personally knelt in prayer on behalf of my Protestant playmates, which they found enormously entertaining.
The touchier question of "converting the Jews" is handled by the movie so tactfully that it is impossible not to be charmed. The key performance here is by Pollak, as a rabbi whose counterpoint to Pete's quest involves understated reaction shots and instinctive sympathy and humor. When the Jacobsons invite Pete over for lunch, he makes the sign of the cross and when the rabbi asks why he's doing it (the unstated words are "at our table"), Pete explains solemnly, "It's like picking up the phone and being sure God is there." Earlier, during his first visit inside the synagogue, Pete is surprised to find no crucifix hanging from the ceiling, and confides to the rabbi: "Sometimes I think of climbing up and loosening the screws and letting him go." The movie cuts between Pete's quest, which is admittedly a little cutesy, and the completely convincing marriage of his parents, Joe and Margaret (Bonnie Hunt). These are (I know) actors who grew up in Chicago neighborhoods and were raised (I believe) as Catholics, and they are pitch-perfect. Note the scene where Hunt is driving most of her eight kids to mass and the troublesome Seamus is making too much noise in the back seat. Still driving, she reaches out to him and beckons him closer, saying, "Come closer...come on, come on, I won't hit you," and then smacks him up alongside the head. Every once in a while a movie gives you a moment of absolute truth.
Danny has leukemia, which he explains solemnly to Pete, who is fascinated. Danny's mother is worried about her young son spending so much time with Pete, but the rabbi observes it may be Danny's last chance to act like a normal kid. The "quest" involves such tests as swimming out to a buoy in Lake Michigan, and while we doubt that, even in innocent 1976, second-graders were going to the beach by themselves, we understand the dramatic purpose.
The most fraught scenes in the movie involve the synagogue's decision to thank the O'Malley family after Joe risked his life to save Danny. They settle on a scholarship for Patrick, the oldest O'Malley boy, and the rabbi is startled when Joe turns it down in anger. Joe tells his wife: "It's about the Jews helping out some poor Roman Catholic family so they can go on TV and get free publicity." Is this anti-Semitism? No, I think it's tribalism, and Joe O'Malley would say the same thing about the Episcopalians, the Buddhists or the Rotary Club. Bonnie Hunt's response is magnificent: If Joe doesn't let his son accept the scholarship, "So help me God, when you come home at night, the only thing colder than your dinner will be your bed." "Stolen Summer" is a film combining broad sentiment with sharp observation, although usually not in the same scenes. I don't know if writer-director Jones came from a large Irish-American family on the North Side, but do I even need to ask? The movie even has Brian Dennehy, patron saint of the Chicago stage, as the parish priest. In a time when so many big-budget mainstream movies are witless and heartless, "Stolen Summer" proves that studios might do just about as well by holding a screenplay contest and filming the winner.
This message came to me from a reader named Peter Svensland. He and a fr...
A review of the newest Netflix YA horror series starring Uma Thurman and Tony Goldwyn.


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On my reading list – right now. Stefan Stenudd's book – "Aikido – the Peaceful Martial Art". Very interesting! Aikido, for me – and almost all who practice it – is an integrated life philosophy. This book deepens the understanding on all aspects of it, in idea and practice.
Category: Aikido
Mika Loves Emoji | #MikaTheHero
His last obsession is an Emoji Encyclopedia I got hold on at the February Annual Book Sale. This message I got today on my way to introduce Aikido to a group of students from my workplace (a secondary school, substitute teacher on call). I interpret it as a story with the message – "Good luck, daddy! Reach high!". Thanks, Mika! All went fine!
A night out with the club | #aikido
Tonight we had a bonus Aikido training, focused on intense Kokyo Nage (for the nerds to know …). So. Fun! Then we hanged out at the Dojo for some extended socializing, before hitting town and ending up on the premier finer beer spot downtown (no brands mentioned …). Great to share time in something else than your Keiko Gi (nerdiness… AGAIN – your training gear …), off the mat, some time! So much to share, so much to love – and that is spelled Aikido, Life and Universe! O'Sensei, the founder, would say – "well, that's the same", meguess ……
Projects 2019 – part one | #projects
Today I start a series of blog posts digesting what I intend to accomplish in all walks of life for the rest of the year. Listing a line of projects, big and small, bold and safe. Personal – health and work First of all – health! Still, I am in process to get to full health. For the moment, I have 25 percent sickness degree, to which I will test if it's possible to work at maximum 30 hours of 40 of the week. I continue to work as a Substitute Teacher at Fria Läroverken in Norrköping, but so far…
Steps | #health
WHO recommends 10k a day. Today – a peak! Mika preschool leaving and getting, a meeting other side of town, then Aikido class. Yay! Sleep well, folks! I will!
Aikido training from yesterday | #aikido #blog31
Yesterday night I was at the aikido training as usual (training Mondays and Wednesday). My Sensei took some photos, and caught me in the act! Behold!
Comeback in the yoga studio | #yoga #blog31
After some months, I made a comeback today at the Yoga Studio (NKYC – Norrköping Kundalini Yoga Center). I really felt I needed it! These are the cornerstones for my wellbeing – Aikido, Running and Yoga!
I graded tonight! I have now 2 kyu! | #aikido
After many years, I have now graded to 2 kyu in Aikido (Takemusu Aiki, Iwama Ryu). Last time I graded was in May 2010, so it was about time! So many other things has happened in my life, coming in between me and my aikido development. But, tonighg was the night! "You can be happy and proud!", the grading committée chairman Leif Kinnersjö, chief instructor emeritus, 6 dan, said. And so I am! Behind me in the photo, I feel Morihei Ueshiba, a k a O'Sensei and Aikido founder, smiling. Thank you for giving me this way of life and…
10. J as in Japan! | #Wishlist2017
36 images of Mount Fuji in different contexts and from different views, from the artist Hokusai – where you most certainly recognize the one on the top left. The Great Wave of Kanagawa. One of the most spread artworks, yes – pop art in its true sense. But, I want to see Mount Fuji. Live! Japan, certainly, is on my Bucket List! A deep wish to go there! And yes, it's not a secret – my passion for Aikido, the japanese Budo form. An integrated part of my life, where Aikido, metaphorically, is a core sense and expression of my…
A Sense of Belonging – The Aikido Community | #CommunityWednesday #Aikido
Tonight I was, as usual on Wednesdays, at the Dojo and trained. Now, approaching bed, I check my Insta flow. I stumbled upon this! You find Aikido there, at right! Oh, this is nerdery. But what to expect? Yes, exactly! I am Aikido! We are spread over the world, and that is a strong feeling. In a sense, it becomes a universal language, similar to music. An understanding beyond words, a connection. And coming with the Radical Inclusiveness I experience with Aikido culture, I can really subscribe to the sentiment – "Aikido – the Art of Peace"! — (Source: linked…
Succession in our Aikido club | #Aikido
After many years of serving as a chairman of our Aikido and Judo club IF Dojo Norrköping, Leif Kinnersjö (6 Dan Aikido, practising Aikido since the seventies), decided to step down and hand over the leadership. And that is to Kimmo Osen, 4 Dan. Good luck, Kimmo! You're a great spirit. And thank you, Leif! I know you will get back this Fall (Leif was injured when he was working with some stuff, and had an operation, now in rehab), just to train with us. It has been a sheer pleasure to take part of your vast knowledge and experience of…
Equal Opportunities | #CommunityWednesday #WomensDay
Today we take notice of all the women of the world. International Women's Day. We still have a long way to go to get a society where Equal Opportunities exist, and where universal human rights are respected in practice. My contribution is to foster my kids, so they can carry the message and live the spirit – a work I do together with my beloved woman, Karin. Another sphere of influence is through my Aikido. In our club, right now, we have two active women. One more senior, who have been practicing Aikido since she was a little kid. And…


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Thunderstorm Asthma Risk High For Migrants
Photo: theguardian.com.au
Thunderstorm asthma is a major respiratory problem which affects some people, and can be fatal. It occurs when stormy winds and moist air cause large grass pollen to break into very tiny pieces, small enough to be inhaled.
The time of highest risk is between 1 October and 31 December. In 2016 there were 2,000 emergency calls for ambulances in three hours. Ten Victorians died from it, and hundreds were hospitalised.
A survey by Asthma Australia showed that 4 in 10 people affected in the 2016 epidemic did not have a previous history of asthma. Of the ten who died, six were originally from India or Southeast Asia.
A major study published in the Lancet Planetary Health journal in June says that while people of Asian or Indian ethnicity make up 25% of the Melbourne population, 39% of hospital admissions were from this group.
Dr Naghmeh Radhakrishna, a respiratory, sleep and allergy specialist at Melbourne's St. Vincent's hospital, told SBS News that Asian people generally have a low prevalence of hay fever and asthma, but that increases after they move to Australia. This may be because they were not previously exposed to allergens like ryegrass, which is very common in southeastern Australia.
Anyone with asthma symptoms should contact a doctor to make an asthma action plan, keep a Ventolin or Asmol inhaler handy, and stay indoors during forecast danger periods.
The government operates a thunderstorm asthma forecast system during the danger period, combining the forecasting of a certain uncommon type of thunderstorm and grass pollen counts.
For translated information visit healthtranslations.vic.gov.au, type "Thunderstorm Asthma" in the Search box, and choose your language from the dropdown menu.
Thuy P
- Joint Agreement For Airport Rail Link
- Experts Call For Funded Dental Care
- New Tech To Stop Number Plate Theft
- Fatigue Test For Drowsy Drivers
- Online Safety Campaign Tackles Bullies
- Search On For Metro Tunnel Artwork
- New Tech To Stop Number Plate Theft
- Joint Agreement For Airport Rail Link
- Fatigue Test For Drowsy Drivers
- Online Safety Campaign Tackles Bullies
- Experts Call For Funded Dental Care


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- Sports News : Biggest Pacific Games team ever for Cook Islands [18/04/2019 - Cook Islands]
- News Feature : Follow the money: how foreign aid spending tells of Pacific priorities [18/04/2019 - Australia]
- Business News : Cook Islands Finance Minister rejects more cash for Agriculture [18/04/2019 - Cook Islands]
- News : Vanuatu Police chief sacked [18/04/2019 - Vanuatu]
- News : Nauru former president regrets signing offshore processing deal with Julia Gillard [18/04/2019 - Australia]
- News : Prince William to visit Christchurch terror attack survivors next week [18/04/2019 - New Zealand]
- Sports News : Captains set for HSBC Kitakyushu Sevens in Japan [18/04/2019 - Japan]
- Sports News : Draw for U-16 & U-19 Women's championships complete [18/04/2019 - New Zealand]
- News Feature : Stress, overtime, disease, contribute to 2.8 million workers deaths per year, reports UN labour agency [18/04/2019 - Switzerland]
- Business News : Fijian government commences national minimum wage and wages regulation review [18/04/2019 - Fiji]
- News : PNG PM ONeill accepts resignation of Attorney General Davis Stevens [18/04/2019 - Papua New Guinea]
- News : Wale and Sogavare the two candidates confirmed for Solomon Islands prime ministerial election [18/04/2019 - Solomon Islands]
- Sponsored : Oceania National Olympic Committees (ONOC)
Samoa's Prime Minister Tuilaepa Sa'ilele Malielegaoi and his Fijian counterpart Voreqe Bainimarama have had a rocky relationship over the years.
But the opening of a new chapter in the bilateral relationship began last year with Tuilaepa's state visit to Fiji, and with the Fiji Government's recent appointment of an ambassador to Samoa.
Fiji's new roving Ambassador to Samoa, Ratu Seremaia Tuinausori Cavuilati presented his credentials to the Head of State, His Highness Tuimaleali'ifano Sualauvi Vaaletoa II.
Speaking to the Samoa Observer, Ratu Seremaia said presenting his credentials follows on from the overall desire between the two leaders to come closer to one another at a political level.
"It was a historic visit by Prime Minister Tuilaepa as far as the relationship between Samoa and Fiji is concerned. So Prime Minister Bainimarama welcomed Tuilaepa, although his initial visit was for the celebration of the University of the South Pacific's 50 years celebration," he told the Samoa Observer.
"The Fiji Government took that opportunity to host him in a state visit. It brings hope, and Fiji has encouraged me to present my credentials here."
Ratu Seremaia said his work is to be the bridge between the two countries in terms of assistance that they can give each other, whether it's at the political, technical or official level.
"Trade is a very important aspect of our relationship. At the moment, Fiji would like to explore that opportunity. We know that Samoa is closely linked to New Zealand and there are imports from there, so we would like to explore opportunities with our private sectors.
"We will be meeting with the Samoa Chamber of Commerce and have a general discussion on areas in which Fiji can assist in trade. We don't have a bilateral trade agreement at the moment, so that is something we need to explore."
He said Fiji is able to assist through capacity building in health, education, and other sectors and Fiji is open to share its knowledge to all Samoans.
"Fiji has been blessed with assistance from international communities and organisations, and of course our development partners, area of capacity building in education, health and other sectors," he said.
"We have been producing people to contribute to Fiji's development, and we also have the capacity to help out. For example, we now have a Fiji Volunteer Scheme, where our retired teachers are being posted to island countries like Tuvalu, Nauru, Republic of Marshall Islands, and also on health, nurses in particular. Of course, we have the University of the South Pacific, Fiji National University and University of Fiji.
"We also open our doors to study visits and also special training; we have the FNU for marine engineering, for special technical and vocational skills which are currently being utilised by Island countries like Kiribati, Tuvalu and also in collaboration with the police agencies boarder control."
Ratu Seremaia said his role is to really understand Samoa better before taking any further step to explore whether it's in trade, tourism, capacity building.
"Fiji is trading with Melanesian Group of companies, but we need to look this way as well. At the moment our private sector is taking the initiative as well, exploring where our trade agreements can help in the areas that haven't been covered or explored."
He added his work is to also look at Fijians living abroad, and ensure that they are working legally in the country they are in.
"We understand that here in Samoa there is quite a sizeable number working in the hospitality industry, domestic workers as well, so we would like to get to them, and their leadership, because we know they have associations so we can relate to them first of all to abide by the laws of Samoa, as well as to look at their well-being."
Ratu Seremaia will be based in Suva, and hopes to visit twice a year, depending on the availability of resources.
News feature
Pacific Islands News Association
Who & What is PINA?
Member Countries
Media Freedom
PINA Convention
Communications Initiative
International News Safety Institute (INSI)
Media Helping Media


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Contact Us
- Phone: (512)869-1310
- Email:
- Mailing Address: 811 Sun City Blvd Georgetown TX 78633
Our Church Family gave $206,950 to missions in 2018, as well as supported two mission trips to Honduras to drill fresh water wells.
Outreach is part of our DNA. Jesus' command in Acts 1: 8 is to be His witnesses in Jerusalem, Judea, Samaria and to the ends of the earth. For us, this means that we are to begin at home but also to share Christ's love through living out our Values to the ends of the earth.
Our approach is to partner with benevolent and mission agencies that are making great impact in sharing the Gospel through specific emphases as well as through providing "a cup of water in Jesus' name".
Our Church Family is committed to compassionate outreach, not only by helping within our community, or just our local Georgetown area, but also across America and across the globe.


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Tech Enthusiasts Needed
Budget ₹12500-37500 INR
We need someone who is comfortable with creating list based articles for our blog. The articles shall be around 1800-2000 words long and payment will be flat Rs. 500 per piece.
If you're interested to work with us, please jot down a 200-word review or preview of anything tech-related and send it to us. It'll help us determine if you tick all the boxes and save everyone some time.
Freshers may be considered as long as English is their forte. Come be part of our team. Good Luck!
4 freelance font une offre moyenne de ₹13194 pour ce travail
Hello I am an experienced Academic Research paper and Business report writer. Education: I have done Masters Business marketing management and also completed Masters in English Literature. Experien Plus
Hi! I will write a review of a certain personal computer part, called the graphics card. Please only start the word count after the line return. Thank you! The GeForce RTX 2080 Ti is the newest flagship GPU from Nvidi Plus
Hi, I am Sahas from Chandigarh, India. I have 1 year of experience in tech blog/article writing. I have been researching about tech from the previous 10 years and I can write very well. I scored 94% marks in Class 12 Plus
I have excellent writing skills. Please see my complete profile for my qualifications. If you have any questions, feel free to e-mail me. I look forward to working with you! We can discuss a price. They ask me to creat Plus


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i am opening a pub which will be knkwn as MS PUB&GRILL. It has to look nice not to creative and not to simple
i have two video clips (2 min and 5min) with bad voice. recorded by phone.
I am going to collect 22 real estate sites that I am dealing with right now. Site name, blog content, new information, phone number, email, address, We have to finish this by April 27th. I have hired gurus from Europe.
i want to make a 3d video of my product wich is an android tv box i want to make a video like the one i have uploaded but looking more professional. i want customer understand that using this tv box you will be able to watch tv channels movies and tv shows. you can make the tv box in 3d connected to a tv and in this tv we will put some video shots of my apk wich will show to customers what they wi...
I want to model the flow on wheel tyre in Ansys fluent
I need someone who can make 3d products with zakeke custom builder. The products are very simple. Bowls, watches, pillows, etc.
Mechanical Engineer Required for Mechatronics PBL
Necesito que escriban algunos artículos sobre Bombas de Vacío, hay que aclarar que no me refiero a los artículos eróticos. Yo pasaría el guión y la estructura, necesito alguien que sepa sobre el tema. La primera fase del proyecto consiste en 7 artículos de 1000 palabras cada uno. la Home Page de 2000. Puedo pagar hasta 13€ el artículo de...
*Must have unique designs * 5 PDF files in US Letter size (8.5"x 11") - High resolution (300dpi) file without watermarks. (ZIPPED FILES) * 2 ZIPPED files * See attached images for sample layouts
Looking for an Instagram SMM coach to boost our profile and get active influencers to promote our brand and our posts.


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About Us
PACE IT EDUCATIONAL INSTIUTION SOCIETY is located in H.No.1-9-837, Top of Hind Bakery, Tirumala Talkies ' X' Road, Nizamabad District , Telangana State. PACE Educational Institutions society is established in the year of 2000 with a motive to provide Employable skill which would enable unemployed youth in getting employment in various sectors Like ITES, Banking & Textile etc. The Society is registered under the Andhra Pradesh Society Act. 35/2001 with registration Number. 492/08.
   PACE Educational Institutions was already executed many Government & private Projects for Skill Development and Placement Linked Training Programs in Garment making , Banking Sectors & ITES . PACE was already trained upto 10000 youth in various place of Andhra Pradesh state. Pace Educational Institutions is tied up with many organizations for the placement of Unemployed youth in many different sectors like ITES, Banking & Textiles etc.. PACE also encouraged many number of unemployed youth for getting self employment .
To Produce quality Life Oriented Education to the youth , which will make good character person in the society and posses effective skill development & Employable skills which will improve the self confidence of the youth for getting the placement in different sectors.
To be recognized as world class center for technical skill development that produce competent and productive youth as per industries requirements.
- Registered No. 492/08 under A.P. Society Registration Act.35/2001, Government of Andhra Pradesh.
- Registered VTP , Under National Council Vocation Training (NCVT) , Under Modular Employable skill (MES), SDIS of Ministry of Skill Development Entrepreneur Department , Government of India.
- Accreditation with NSDA(Nation Skill Development Academy) , Government of India.
- Mou with MEPMA, Telangana, for implementation of ESTP component of,NULM, Government of India.
- Empanneled under NDLM , Government of India.
- MOU with Employment & Training Department, Government of Telangana.


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