{'fraction_non_alphanumeric': 0.0335508459894901, 'fraction_numerical': 0.021770514523300803, 'mean_word_length': 5.040460411580049, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 4, 'https://': 1, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Population pharmacokinetics and pharmacodynamics of dobutamine in neonates on the first days of life

Aims To describe the pharmacokinetics (PK) and concentration‐related effects of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=535 in critically ill neonates in the first days of life, using nonlinear mixed effects modelling. Methods Dosing, plasma concentration and haemodynamic monitoring data from a dose‐escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5–20 μg kg−1 min−1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors. Results Twenty‐eight neonates with median (range) gestational age of 30.4 (22.7–41.0) weeks and birth weight (BW) of 1618 (465–4380) g were included. PK data were adequately described by 1‐compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h−1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model. Conclusion In the postnatal transitional period, PK of dobutamine was described by a 1‐compartmental linear model, CL related to BW and PMA. A concentration–response relationship with haemodynamic variables has been established.


| INTRODUCTION
Dobutamine is a β 1 -adrenoceptor (AR) agonist catecholamine, designed to increase cardiac output (CO) without evoking vasoconstriction or tachycardia. 1 In critically ill neonates, inotropic therapy with dobutamine is often used because of low blood pressure (BP), signs of low organ perfusion, or CO measured at echocardiography. 2 Early administration of dobutamine to preterm infants during the first days of life has been found to stabilise transitional circulation. [3][4][5][6] The pharmacokinetics (PK) of dobutamine in the paediatric population is described in children rather than neonates. [7][8][9][10][11][12][13] Except for 1, 10 the studies indicate first-order elimination kinetics within the dose range of 2.5-10 μg kg −1 min −1 for neonates and 2.5-17.5 μg kg −1 min −1 for infants and children. Plasma clearance (CL) rate is widely variable. [7][8][9][10][11][12][13] The only study describing PK of dobutamine in neonates, reported mean (standard deviation) CL of 90 (38) mL min −1 kg −1 with variability independent of gestation and birth weight (BW). 13 However, the sample size was small and postmenstrual age (PMA), a potentially better marker for maturation of elimination processes, was not explored. 13 In the dose range of 2.5 to 7.5 μg kg −1 min −1 the elimination of dobutamine was linear 13 but as doses rise above this range the kinetics may become nonlinear. 10 Studies on pharmacodynamic (PD) effect of cardiac performance have mostly assessed dose-response relationship in doses up to 10 μg kg −1 min −1 . 13,14 CO increases at low doses, but heart rate (HR) or BP require larger doses to be affected. 13,14 However, such associations have not been consistently found 15 that may be in part due to wide variation in CL, requiring simultaneous analysis of actual plasma concentrations and response. Considering the immaturity of the cardiovascular system in neonates, a plateau of the effect on CO and BP at doses of 7.5-10 μg kg −1 min −1 in children 9 may not occur in neonates and thus PKPD in larger doses needs to be studied.
We aimed to describe the PK and PD of dobutamine in simultaneous PKPD modelling in critically ill preterm and term neonates  A prospective 2-centre study was performed in Tallinn Children's Hospital, Tallinn, Estonia and Tartu University Hospital, Tartu, Estonia.
All neonates hospitalized to NICU within the first 72 h of life from April 2016 to December 2017 were screened for eligibility. We included neonates who needed inotropic therapy according to the decision of the treating physician (based on echocardiographic assessment, cerebral regional oxygen saturation (rScO 2 ), mean arterial blood pressure (MAP), acid-base balance, serum lactate and capillary refill time), and had arterial catheter and/or central venous catheter in place on clinical indication. Study exclusion criteria were congenital malformations with potential impact on haemodynamic (HD) response to inotropic therapy (congenital heart disease), congenital hydrops, other unresolved cause of low blood flow (air leak), known metabolic disease, situations where the treating physician considered a different vasoactive treatment necessary or dobutamine contraindicated and hypersensitivity to dobutamine or any other component of the study medication. Written informed consent was signed by parents or guardians before study inclusion.
2.1 | Study drug administration and PK sampling Dobutamine 12.5 mg mL −1 concentrate for solution for infusion (Dobutamine Claris, Claris Lifesciences Limited, UK) was diluted with 0.9% NaCl to a concentration of 1.25 mg mL −1 within 20 min before administration. Study medication infusion was started immediately What is already known about this subject • Dobutamine clearance has high interindividual variability in neonates and children.
• Individual plasma concentrations are linearly related to the doses, with increasing uncertainty at higher levels.

What this study adds
• Describes pharmacokinetics and pharmacodynamics of dobutamine in postnatal transitional period using population nonlinear mixed effects modelling.
• For clearance 62% of between subject variability is related to birth weight and postmenstrual age.
• Dobutamine effects to central haemodynamic parameters and cerebral fractional tissue oxygen extraction are concentration related.
after the first echocardiographic assessment at a dose of 5 μg kg −1 min −1 and raised by 5 μg kg −1 min −1 approximately every 30 min to a maximum of 20 μg kg −1 min −1 . Dose change times were recorded with the precision of the nearest minute. Individual dose escalation maximum was decided based on echocardiographic and clinical findings. Dose-limiting effects of the study medication were (i) persistent tachycardia (HR >200 min −1 in preterm and >180 min −1 in term neonates) or arrhythmias; (ii) no additional effect of the last dose increase; or (iii) sufficient effect of the last dose. To ensure adequate intravascular volume, all neonates received a bolus of 10 mL kg −1 of normal saline over 10 min, unless any fluid bolus was already received within 4 h prior to study inclusion. Further cardiovascular support with volume bolus and inotropes other than study medication was provided on the decision of the treating physician without any restrictions in the study protocol.

| Patient monitoring
Echocardiography was performed before the start of treatment and approximately 20-30 min after each dose escalation, and left ventricular ejection fraction (LVEF) and CO of right and left ventricle (RVO, LVO) were measured. 18 Patent ductus arteriosus diameter was measured by 2D imaging at the narrowest point. Intra-and interobserver variability was assessed according to a recent recommendation. 19 HR, BP, peripheral arterial oxygen saturation (SaO 2 ) and rScO 2 were monitored continuously and recorded with 2.5-s intervals by BedBase software (University Medical Center Utrecht, the Netherlands). Demographic data, birth history, Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE II), 20 therapeutic interventions and laboratory data were collected from hospital records. All neonates were monitored for adverse events for 7 days after the end of treatment with study medication.  Simultaneous PKPD modelling was undertaken with HD parameters as PD effect, using the final linear PK structural model with Hill coefficient and PMA 50 fixed to values estimated from PK data ( Table 2). HR, MAP, SaO 2 and rScO 2 data recorded during a 15 min period (5 min before and 10 min after each dose change) were selected and averaged over 1 min. Cerebral fractional tissue oxygen extraction (cFTOE) was calculated as a ratio: (SaO 2 -rScO 2 )/SaO 2 .

| PKPD analysis
Adding an effect compartment with a first-order equilibration rate constant (k eo ) to the final PK structural model was tested with for HR, MAP and cFTOE PKPD models, assuming that the amount of drug distributing into the effect compartment does not influence the overall PK (Equation 3): where C is the plasma concentration, C e is the effect compartment concentration and k eo is the equilibration rate constant between effect and observed (plasma) compartments.
Baseline HD parameter values were estimated. Changes in HD parameter values were explored using linear (Equation 4), E max (Equation 5) and sigmoidal E max (Equation 6) models: where E ij is the j-th observed HD parameter value at the corresponding plasma or effect compartment concentration (C ij ) of the i-th individual, E 0,i represents the estimated baseline value, SL i is the slope of the linear relationship between E ij and C ij for the i-th individual, E max , i is the estimated maximum HD parameter value for the i-

| RESULTS
Thirty-one neonates were recruited and data from 28 of them were included in the final analysis. The reason for omission was therapeutic hypothermia, considered to possibly affect the PK of dobutamine, in 2, and withdrawal of parental consent in 1 case. Demographic and clinical data of the study patients are presented in Table 1. The main underlying diagnoses were respiratory distress syndrome (14), early onset neonatal sepsis defined as clinical and laboratory signs of infection with antibacterial therapy for more than 3 days (8, none were culture positive), perinatal asphyxia (2), meconium aspiration (2) and foeto-foetal transfusion syndrome (2).  Figure 1.

| Dobutamine PK and PD
The PK data were described by 1-compartmental linear structural The final linear PK model parameter estimates are presented in Table 2, basic GOF plots in Figure 2 and prediction-corrected VPC in Figure 3.
Concentration-related changes in RVO and LVEF were best described with linear PD models and in LVO with a sigmoidal E max model (Table 3). Continuously measured HD parameters were best described with a sigmoidal E max model with effect compartment equilibration rate constant with mean effect time (k eo -1 Á 60 min) of 9 min for HR and without effect compartment equilibration rate constant for MAP and cFTOE (Table 3). Final PKPD model parameter estimates for RVO, LVO and LVEF are presented in Table 4 and for HR, MAP and cFTOE in Table 5       θ, population typical parameter value; NE, not estimated; BSV, between subject variability; a presented as coefficient of variation, calculated as: (square root of ω 2 )Á100%; CL, clearance; V, volume of distribution; E 0 , estimated baseline value of PD parameter; SL is the slope of the linear relationship between effect and concentration; γ, steepness of concentration-effect relationship; EC 50 , concentration at half-maximal effect; E max , estimated maximum value of PD parameter

| Clinical outcome
In previous paediatric studies an extremely wide BSV in dobutamine plasma CL has been noticed 7,9 and explained by variation in sulfoconjugation and renal function. 11 Maturation of these elimination processes is not well understood. In the present study, the variation in CL was well described with allometric scaling to population median BW with power coefficient of 0.75 and exponential E max maturation function with estimation of PMA 50 and Hill coefficient from PK data. 21 The estimated mean parameter values of 37.4 weeks for PMA 50 and 2.67 for Hill coefficient are similar to those identified for CL maturation in other drugs in neonates. 21 This approach yielded a shared BSV coefficient of 29% for CL and V, which is notably smaller than described earlier for dobutamine CL.
There is 1 study reporting highly variable V of dobutamine with a mean (range) of 1.14 (0.09-5.65) L kg −1 in paediatric patients aged 1 month to 16 years, 12 the mean value being higher than reported in adults (0.202 L kg −1 ). 25 The typical value for V of 5.29 L 1618-g −1 or 3.27 L kg −1 in the present study population is even higher than the paediatric study. 12 Higher V of a water-soluble agents in neonates in their first days of life can be explained by significantly higher total body water content, which undergoes major reduction (accompanied T A B L E 5 Final pharmacokinetic-pharmacodynamic (PKPD) model mean (standard error, SE) parameter estimates for heart rate (HR), mean arterial blood pressure (MAP) and cerebral fractional tissue oxygen extraction (cFTOE)

| Dobutamine PD
Dobutamine is known to increase HR and CO in neonates, whereas the effect of BP varies from no effect to minor increase. [7][8][9]13,14,29 According to our results, these effects occur at different concentra- also been shown in critically ill children. 8 Although with limited efficacy, dobutamine has also been shown to increase superior vena cava flow, which is considered to reflect cerebral blood flow. 29,31 The present study describes dobutamine effect to cFTOE, as a surrogate for cerebral blood flow. Decrease in cFTOE with dobutamine may refer to increase in cerebral blood flow.
The aim of neonatal circulatory management is to prevent cerebral hypoperfusion particular in preterm neonates where the cerebral autoregulation may be absent. Although the role of inotropes in prevention of prematurity-related brain injury has been difficult to establish, there is some evidence that early administration of dobutamine may be relatively safe. In a foetal sheep hypoxia-induced brain injury model, dobutamine pretreatment decreased neuroinflammation in the white matter and caudate and did not exacerbate cerebral injury or inflammation in the sham group. 4 In a neonatal study dobutamine was found to be associated with greater increase in systemic blood flow, reduced rates of severe periventricular/intraventricular haemorrhage and fewer disabilities at age 3 years, but combined rates of death or disability similar, compared with infants treated with dopamine. 29,32 The rate of serious cerebral complications in our study patients born before 32 weeks of gestation (2/16 for intraventricular haemorrhage III-IV and 2/16 for periventricular leucomalacia) was comparable to that described in previous studies in extremely and very preterm infants receiving early dobutamine treatment. 29,31 The present PKPD analysis included most of the well described effects of dobutamine. 33 Describing population HD effect of dobutamine as a function of concentration gives the confidence that at the dose range of 5-20 μg kg −1 min −1 the medication is effective.

| Limitations of the study
The limited number of patents, and limited PK sampling, did not yield informative data on V (hence BSV could not be separately estimated for CL and V). As the smallest neonate weighed <500 g, only 3-5 plasma samples could be taken for research purposes, although an analytical micro-method for plasma sample volumes of 20 μL was developed. 16 Having only a few PK samples >200 μg L −1 in the dataset, we may not have been able to capture this end sufficiently.
The relatively small number of patients limited the covariate analysis. Although adding postnatal age, concomitant medications, severity of illness/status in covariate analysis did not improve PK model fit in our study, a larger and more variable study sample may be needed to draw firm conclusions. 34 In neonatal PK studies, an important limitation/source of residual error is drug administration accuracy. Dilution of the formula, low infusion rates and large dead space may lead to discrepancy between the prescribed and actual infusion rates, resulting in PK observation residual error of >50%.
Nevertheless, this considerably homogenous neonatal study population allowed us to model PK of dobutamine, describing the maturation of CL with PMA, and rich PD effect sampling allowed identification of relationships between concentration and HD effects with acceptable accuracy. Moreover, this study was conducted in real-life conditions, e.g. critically ill neonates on their first days of life, with all related challenges.
In conclusion, within the clinically relevant dose range, dobutamine PK in neonates is linear. BSV of dobutamine CL is partly explained by PMA and BW. Dobutamine effects on HD parameters as CO, LVEF, HR, MAP and cFTOE are concentration related during the period of transitional circulation. High BSV of the PD response suggests need for individual dose titration rather than targeting specific dosing regimen in neonates receiving dobutamine for stabilization of transitional circulation.