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Development of a Paediatric Population-Based Model of the Pharmacokinetics of Rivaroxaban

Background Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. Objective The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0–18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Methods Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration–time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations. Results Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight <40 kg) were lower than the 90 % confidence interval threshold of the adult reference model and, therefore, indicated that doses in these groups may need to be increased to achieve the same plasma levels as in adults. For children with body weight between 40 and 70 kg, simulated plasma pharmacokinetic parameters (C max, C 24h and AUC) overlapped with the values obtained in the corresponding adult reference simulation, indicating that body weight-related exposure was similar between these children and adults. In adolescents of >70 kg body weight, the simulated 90 % prediction interval values of AUC and C 24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg. Conclusion The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients. Electronic supplementary material The online version of this article (doi:10.1007/s40262-013-0090-5) contains supplementary material, which is available to authorized users.


Study B: Absolute bioavailability
A single-centre, randomized, open-label, three-way crossover study evaluated the pharmacokinetics of rivaroxaban single 5 mg or 20 mg immediate-release tablet doses in comparison with rivaroxaban 1 mg administered as a 30-minute intravenous infusion in 12 healthy male subjects (aged 21-46 years) [2]. The drug was administered under fasted conditions. Compared with the 1 mg intravenous infusion, bioavailability of the 5 mg tablet dose was 112 % (95 % confidence interval [CI] 97-129), whereas that of the 20 mg dose was 66 % (95 % CI 57-76). When the 20 mg dose was compared with the 5 mg dose, bioavailability was 59 % (95 % CI 51-68). The higher than 100 % bioavailability of the 5 mg tablet compared with the intravenous infusion was not significant because 100 % is included in the CI and, therefore, bioavailability for the 5 mg tablet was considered to be complete. In addition, 112 % (i.e. >100 %) is considered a chance finding because detailed audits of dosing and bioanalytical procedures did not reveal any errors. Results of this study indicated that pharmacokinetic parameters (e.g. area under the plasma concentration-time curve [AUC], maximum [peak] plasma drug concentration [C max ] and time to reach maximum [peak] plasma concentration following drug administration [t max ]) increased with dose but were less than dose proportional [2]. The rates of treatment-emergent adverse events were similar between the three different dose groups.

Study C: Pharmacokinetics across a wide dose range
A placebo-controlled, dose-escalation study investigated plasma concentration-time profiles for rivaroxaban in 108 healthy male subjects (aged 19-45 years) after single oral doses of rivaroxaban ranging from 1.25 mg to 80 mg (dosage forms used were: 5 mg and 10 mg, both as tablet and solution, and 20 mg, as tablet) [3]. Rivaroxaban had predictable 3 pharmacokinetic characteristics for both formulations and across the wide range of doses.
After administration, rivaroxaban was absorbed rapidly (t max 2 hours for oral tablet).

Study D: Absorption from proximal and distal small bowel and ascending colon
For the evaluation of colonic absorption of rivaroxaban, a single-centre, non-randomized, non-placebo-controlled, non-blinded, crossover study investigated the pharmacokinetics of rivaroxaban 10 mg after single-dose applications: as two 5 mg oral tablets or as granules (from crushed tablets) administered via the Enterion™ capsule to the proximal small bowel, distal small bowel or ascending colon (Pharmaceutical Profiles Ltd., Nottingham, UK) [4].
This capsule enables remote-controlled, site-specific drug delivery and is used to investigate regional drug absorption in the gastrointestinal tract. In addition, a 5 mg solution prepared from rivaroxaban powder was administered to the ascending colon via the Enterion™ capsule [5].

Study E: Food effect on pharmacokinetics of two 5 mg tablets
This study was a randomized, open label, two-way crossover study to investigate the effect of a high-fat, high-calorie meal on safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban 10 mg given orally as two 5 mg tablets in 10 healthy male subjects (aged 19-45 years) [6]. Mean rivaroxaban t max increased from 3 hours (fasted state) to 4 hours (fed state), indicative of slower absorption with the administration of food.
Additionally, mean AUC and mean C max values of rivaroxaban were significantly increased in the fed state.

Study F: Food effect on pharmacokinetics of four 5 mg tablets or one 20 mg tablet
In this single-dose, non-blinded, randomized, non-placebo-controlled crossover study, the effect of a high-fat, high-calorie or high-carbohydrate meal on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban 20 mg given either as four 5 mg tablets or one 20 mg tablet was investigated in 12 healthy male subjects (aged 19-44 years) [6]. No relevant pharmacokinetic differences were observed between the two dosing regimens (four 5 mg tablets vs one 20 mg tablet) or between the two types of meals (high fat, high calorie vs high carbohydrate). Mean t max increased from 2.75 hours (fasted) to 4 hours (fed, both dosing regimens). Additionally, mean AUC and mean C max values were significantly higher after food.

Study G: Food effect on pharmacokinetics of one 10 mg tablet or one 20 mg tablet
Two randomized, open-label, two-way crossover studies assessed the effect of a high-fat, high-calorie meal on the safety, tolerability and pharmacokinetics of a 10 mg (n = 24) and 4 20 mg rivaroxaban tablet (n = 22), respectively, in healthy male subjects (aged 19-45 years) [2]. In the 10 mg group, mean plasma AUC and mean C max values were similar in fasted or fed states. The t max was delayed by 0.5 hour after food. In the 20 mg group, AUC was increased by 39 % and C max by 76 % after food. The t max was delayed by 1.5 hours after food.
Safety and adverse event profiles were similar between both doses.

Electronic Supplementary Material: Section 2 Parameters for Absorption from the Gastrointestinal Tract
Differences in the pH of the gastrointestinal tract may alter the absorption profile of acid and alkaline drugs. However, an effect of pH on solubility and permeability in the gastrointestinal tract is not expected for rivaroxaban. Therefore, the pH of the stomach and intestinal tract was not implemented as an age-dependent parameter, and default values of PK-Sim ® were used.
The results of an independent reassessment of multiple data sets on gastric emptying time under fasted and fed conditions suggested that, when explicitly discriminating between both states, gastric emptying time is similar in children and adults [7][8][9][10][11]; however, gastric emptying is typically prolonged in neonates and infants aged 2-24 months owing to the almost constant presence of milk and/or formula in the stomach. The gastric emptying time functions for an average adult under fasted and fed conditions were used for simulations across the entire paediatric age range. In order to represent the average feeding state in the paediatric population, simulations in the fasted state (no lag) and in the fed state were carried out and subsequently pooled for the analysis (see Methods).
Reported small intestinal transit times in neonates and infants are similar to those in older children and adults [12][13][14][15][16][17][18]. Therefore, the small intestinal transit times were not implemented as an age-dependent parameter. By contrast, the large intestinal transit time is significantly shorter in children than in adults [19]. The reported differences are accounted for by using a scale factor for the velocity [cm/h] of drug transport along the large intestine that was established based on the data reported in the literature [19]. It was assumed that there were no differences in large intestinal transit time between male and female children.
Age-dependent differences in intestinal surface area may affect the proportion of absorption and/or the absorption profile of drugs in children. Information about anatomical changes of the intestine (length, radius) is available in the literature [19], whereas information about the ontogeny of the intestinal physiology (relevant for the estimation of the surface amplification owing to the presence of circular folds, villi and microvilli) is sparse. Therefore, the information required for scaling was derived from pharmacokinetic data of two reference compounds, acyclovir and ciprofloxacin, both given orally to children. For these compounds pharmacokinetic data for the children aged 3 days to 7 years were available [20,21].
Analysis of these data suggested a scaling factor of 0.91 for the intestinal surface area of all 6 sections of the gastrointestinal tract for children aged 0-7 years. For children older than 7 years, the scaling factor was 1.
Specific intestinal permeability (i.e. the intestinal permeability normalized to the surface area) in infants aged 1 month to 3 years is similar to that in adults and is only high in infants in the first few days after birth [22][23][24][25]. Therefore, the specific intestinal permeability was held constant at all ages.