Pediatric Physiologically Based Pharmacokinetic Models Research Articles

Physiologically based pharmacokinetic modelling of cefoperazone in paediatrics.

Cefoperazone is commonly used off-label in the treatment of bacterial meningitis and sepsis in children, and the pharmacokinetic (PK) data are limited in this vulnerable population. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict pediatric cefoperazone exposure for rational dosing recommendations. A cefoperazone PBPK model for adults was first constructed using Simcyp V22 simulator. Subsequently, the model was extended to children based on the built in age-dependent physiological parameters, while the drug characteristics remained unchanged. The verified pediatric PBPK model was then utilized to assess the rationality of the common dosing regimens for children at different age groups. Cefoperazone PBPK model included elimination via biliary excretion, glomerular filtration, and organic anion transporter 3 (OAT3)-mediated tubular secretion. 95.2% of the observed mean concentrations and 100% of the area under the plasma drug concentration-time curve (AUC) and peak concentration (Cmax) in adults were within a twofold range of model mean predictions. Good predictive accuracy was also observed in children, including neonates. 50 mg/kg q12h cefoperazone demonstrated effective target attainment in virtual term neonates (<1 month) when the MIC was ≤1 mg/L, adhering to the stringent PK/PD target of 75% fT > MIC. 37.5 mg/kg q12h cefoperazone achieved the common 50% fT > MIC target for an MIC ≤ 0. 25 mg/L in virtual pediatric patients ranging from 1 month to 18 years of age. A pediatric PBPK model was developed for cefoperazone, and it could serve as the basis for deriving rational dosing regimens in children.

Physiologically-based pharmacokinetic modeling of pantoprazole to evaluate the role of CYP2C19 genetic variation and obesity in the pediatric population.

Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically-based PK (PBPK) models are an attractive alternative that can account for physiologic-, genetic-, and drug-specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age-associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration-recommended weight-tiered dosing. Simulated concentration-time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight-tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited.

Prediction of Pediatric Pharmacokinetics for CYP3A4 Metabolized Drugs: Comparison of the Performance of Two Hepatic Ontogeny Within a Physiologically Based Pharmacokinetic Model.

The rapid growth in the use of pediatric physiologically based pharmacokinetic (PBPK) models, particularly for regulatory applications, has focused emphasis on model verification and ensuring system parameters are robust, including how these change with age. Uncertainty remains regarding the ontogeny of some enzymes and transporters, in this study 2 published ontogeny profiles for hepatic CYP3A4 were compared. Clinical pharmacokinetic data on 4 intravenously administered CYP3A4 substrates (alfentanil, fentanyl, midazolam, and sildenafil) used across the pediatric age range was collected from the literature. The PBPK models were verified in the adult population and then used to compare the Salem and a modified Upreti ontogeny profiles for CYP3A4 in terms of parent drug clearance and area under the curve from birth onward. Overall, the modified Upreti ontogeny profile resulted in 15 out of 17 age-related predictions within 2-fold and 12 out of 17 predictions within 1.5-fold ranges of observed values, for the Salem ontogeny these values were 12 out of 17 and 8 out of 17, respectively. The Upreti ontogeny profile performed better than Salem, average fold error and absolute average fold error were 1.14 and 1.35 compared to 1.56 and 1.90, respectively. Identifying the optimal CYP3A4 ontogeny is important for regulatory use of PBPK especially given the number of drugs cleared by this enzyme. This study broadens the evidence from previous studies that Upreti is more favorable than Salem, but further work is needed especially in the neonatal and early infant age range.

Maternal Ezetimibe Concentrations Measured in Breast Milk and Its Use in Breastfeeding Infant Exposure Predictions.

Lactating mothers taking ezetimibe, an antihyperlipidemic agent, may be hesitant to breastfeed despite the known benefit of breastfeeding to both mother and infant. Currently, no data exist on the presence or concentration of ezetimibe and its main active metabolite, ezetimibe-glucuronide (EZE-glucuronide), in human breast milk. Voluntary breast milk samples containing ezetimibe and EZE-glucuronide were attained from lactating mothers taking ezetimibe as part of their treatment. An assay was developed and validated to measure ezetimibe and EZE-glucuronide concentrations in breast milk. A workflow that utilized a developed and evaluated pediatric physiologically based pharmacokinetic (PBPK) model, the measured concentrations in milk, and weight-normalized breast milk intake volumes was applied to predict infant exposures and determine the upper area under the curve ratio (UAR). Fifteen breast milk samples from two maternal-infant pairs were collected. The developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed an analytical range of 0.039-5.0 ng/mL and 0.39-50.0 ng/mL for ezetimibe and EZE-glucuronide, respectively. The measured concentrations in the breast milk samples were 0.17-1.02 ng/mL and 0.42-2.65 ng/mL of ezetimibe and EZE-glucuronide, respectively. The evaluated pediatric PBPK model demonstrated minimal exposure overlap in adult therapeutic dose and breastfed infant simulated area under the concentration-time curve from time zero to 24h (AUC24). Calculated UAR across infant age groups ranged from 0.0015 to 0.0026. PBPK model-predicted ezetimibe and EZE-glucuronide exposures and UAR suggest that breastfeeding infants would receive non-therapeutic exposures. Future work should involve a 'mother-infant pair study' to ascertain breastfed infant plasma ezetimibe and EZE-glucuronide concentrations to confirm the findings of this work.

Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5-95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K. Profiles for OAT3, P-gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5-95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population-specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.

Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion.

Physiologically based pharmacokinetic (PBPK) models are useful in bridging drug exposure in different ethnic groups, and there is increasing regulatory application of this approach in adults. Reported pediatric PBPK models tend to focus on the North European population, with few examples in other ethnic groups. This study describes the development and verification of a Japanese pediatric PBPK population. The development of the model was based on the existing North European pediatric population. Japanese systems and clinical data were collated from public databases and the literature, and the underlying demographics and equations were optimized so that physiological outputs represented the Japanese pediatric population. The model was tested using 14 different small molecule drugs, eliminated by a variety of pathways, including cytochrome P450 3A4 (CYP3A4) metabolism and renal excretion. Given the limitations of the clinical data, the overall performance of the model was good, with 44/62 predictions for PK parameters (area under the plasma drug concentration-time curve, AUC; maximum serum concentration, Cmax ; clearance, CL) being within 0.8- to 1.25-fold, 56/62 within 0.67- to 1.5-fold, and 61/62 within 0.5- to 2.0-fold of the observed values. Specific results for the 5 CYP3A4 substrates showed 20/31 cases were predicted within 0.8- to 1.25-fold, 27/31 within 0.67- to 1.5-fold, and all were within 0.5- to 2.0-fold of the observed values. Given the increased regulatory use of pediatric PBPK in drug development, expanding these models to other ethnic groups are important. Considering qualifying these models based on the context of use, there is a need to expand on the current research to include a larger range of drugs with different elimination pathways. Collaboration among academic, industry, model providers, and regulators will facilitate further development.

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin.

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8mg/kg/day from 0.5 to 2years old, 9.2mg/kg/day from 3 to 6years old, 9.4mg/kg/day from 7 to 12years old, and 8.2mg/kg/day from 13 to 18years old, taken in half for 2-5days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.

Another Step Toward Qualification of Pediatric Physiologically Based Pharmacokinetic Models to Facilitate Inclusivity and Diversity in Pediatric Clinical Studies.

Robust prediction of pharmacokinetics (PKs) in pediatric subjects of diverse ages, ethnicities, and morbidities is critical. Qualification of pediatric physiologically-based pharmacokinetic (P-PBPK) models is an essential step toward enabling precision dosing of these vulnerable groups. Twenty-two manuscripts involving P-PBPK predictions and corresponding observed PK data (e.g., area under the curve and clearance) for 22 small-molecule compounds metabolized by CYP (3A4, 1A2, and 2C9), UGT (1A9 and 2B7), FMO3, renal, non-renal, and complex routes were identified; ratios of mean predicted/observed (P/O) PK parameters were calculated. Seventy-eight of 115 mean predicted PK parameters were within 0.8 to 1.25-fold of observed data, 98 within 0.67 to 1.5-fold, 109 within 2-fold, and only 6 P/O ratios were outside of these bounds. A set of 12 CYP3A4-metabolized compounds and a set of 6 metabolized by other enzymes, CYP1A2 (1 compound), CYP2C9 (2 compounds), UGT1A9 (1 compound) and UGT2B7 (2 compounds) had 56 of 59 and 22 of 25 mean P/O ratios, respectively, that fell within the > 0.5 and < 2.0-fold boundaries. For compounds covering renal, non-renal, complex, and FM03 routes of elimination, 29 of 31 mean P/O ratios fell within the 0.67 to 1.5-fold bounds, including 4 of 5 P/O ratios from newborns. P-PBPK modeling and simulation is a strategic component of the complement of precision dosing methods and has a vital role to play in dose adjustment in vulnerable pediatric populations, such as those with disease or in different ethnic groups. Qualification of such models is an essential step toward acceptance of this methodology by regulators.

Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients.

Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily). Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction. Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group. Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age). Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated. Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co-treatment with 600 mg oral rifampin daily decreased the steady-state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/m2 ) PO BID without rifampin and 230/230 mg/m2 LPV/RTV PO BID with 10 mg/kg PO daily rifampin in pediatric patients. Sixteen mg/kg of super-boosted LPV (LPV/RTV 1:1) PO BID with 15 mg/kg PO daily rifampin achieved simulated LPV troughs >1 mg/L in ≥93% of virtual children weighing 3.0-24.9 kg, which was comparable with 10 mg/kg PO daily rifampin. Super-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children.

Use of Real-World Data and Physiologically-Based Pharmacokinetic Modeling to Characterize Enoxaparin Disposition in Children With Obesity.

Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low‐molecular‐weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti–activated factor X (anti‐Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed‐effects regression models, we observed that 4‐hour anti‐Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose (P = 0.004). To further mechanistically explore obesity‐associated differences in anti‐Xa concentration, a pediatric physiologically‐based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti‐Xa and elimination via heparinase‐mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real‐world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4‐hour anti‐Xa concentrations under recommended, total body weight–based dosing compared to children without obesity owing to reduced weight‐normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat‐free mass weight‐based dosing.

Development and application of a pediatric mechanistic kidney model.

Pediatric physiologically‐based pharmacokinetic (P‐PBPK) models have been used to predict age related changes in the pharmacokinetics (PKs) of renally cleared drugs mainly in relation to changes in glomerular filtration rate. With emerging data on ontogeny of renal transporters, mechanistic models of renal clearance accounting for the role of active and passive secretion should be developed and evaluated. Data on age‐related physiological changes and ontogeny of renal transporters were applied into a mechanistic kidney within a P‐PBPK model. Plasma concentration–time profile and PK parameters of cimetidine, ciprofloxacin, metformin, tenofovir, and zidovudine were predicted in subjects aged 1 day to 18 years. The predicted and observed plasma concentration–time profiles and PK parameters were compared. The predicted concentration–time profile means and 5th and 95th percent intervals generally captured the observed data and variability in various studies. Overall, based on drugs and age bands, predicted to observed clearance were all within two‐fold and in 11 of 16 cases within 1.5‐fold. Predicted to observed area under the curve (AUC) and maximum plasma concentration (Cmax) were within two‐fold in 12 of 14 and 12 of 15 cases, respectively. Predictions in neonates and early infants (up to 14 weeks postnatal age) were reasonable with 15–20 predicted PK parameters within two‐fold of the observed. ciprofloxacin but not zidovudine PK predictions were sensitive to basal kidney uptake transporter ontogeny. The results indicate that a mechanistic kidney model accounting for physiology and ontogeny of renal processes and transporters can predict the PK of renally excreted drugs in children. Further data especially in neonates are required to verify the model and ontogeny profiles.

Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents With Obesity.

Childhood obesity continues to rise in the United States and, with it, the off-label use of metformin for weight loss. The influence of age and obesity on the drug's disposition and exposure has not previously been studied using a mechanistic framework. Here, an adult physiologically based pharmacokinetic (PBPK) model of metformin was scaled to pediatric populations without obesity, with overweight/obesity, and with severe obesity; a published virtual population of children and adolescents with obesity was leveraged during model evaluation. When the pediatric model was simulated in groups aged 10 to 18 years, oral clearance following 1000mg of metformin was higher (≈1200mL/min) in those with obesity and severe obesity compared to the groups without and with overweight (≈1000mL/min). In addition, simulated area under the concentration-time curve in older children and adolescents with obesity and severe obesity was comparable to that in adults with a similar dose-exposure relationship. Overall, simulations using the pediatric PBPK model support the use of adult doses of metformin in older children and adolescents with obesity. Moreover, the virtual population of children and adolescents with obesity offers a valuable tool to facilitate development of pediatric PBPK models for studying populations with obesity and, in turn, contribute information to inform drug labeling in this special population.

Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations.

There has been a significant increase in the use of physiologically based pharmacokinetic (PBPK) models during the past 20 years, especially for pediatrics. The aim of this study was to give a detailed overview of the growth and areas of application of pediatric PBPK (P‐PBPK) models. A total of 181 publications and publicly available regulatory reviews were identified and categorized according to year, author affiliation, platform, and primary application of the P‐PBPK model (in clinical settings, drug development or to advance pediatric model development in general). Secondary application areas, including dose selection, biologics, and drug interactions, were also assessed. The growth rate for P‐PBPK modeling increased 33‐fold between 2005 and 2020; this was mainly attributed to growth in clinical and drug development applications. For primary applications, 50% of articles were classified under clinical, 18% under drug development, and 33% under model development. The most common secondary applications were dose selection (75% drug development), pharmacokinetic prediction and covariate identification (47% clinical), and model parameter identification (68% model development), respectively. Although population PK modeling remains the mainstay of approaches supporting pediatric drug development, the data presented here demonstrate the widespread application of P‐PBPK models in both drug development and clinical settings. Although applications for pharmacokinetic and drug–drug interaction predictions in pediatrics is advocated, this approach remains underused in areas such as assessment of pediatric formulations, toxicology, and trial design. The increasing number of publications supporting the development and refinement of the pediatric model parameters can only serve to enhance optimal use of P‐PBPK models.

Cytochrome P450 enzymes in the pediatric population: Connecting knowledge on P450 expression with pediatric pharmacokinetics.

Cytochrome P450 enzymes play an important role in the pharmacokinetics, efficacy, and toxicity of drugs. Age-dependent changes in P450 enzyme expression have been studied based on several detection systems, as well as by deconvolution of in vivo pharmacokinetic data observed in pediatric populations. The age-dependent changes in P450 enzyme expression can be important determinants of drug disposition in childhood, in addition to the changes in body size and the other physiological parameters, and effects of pharmacogenetics and disease on organ functions. As a tool incorporating drug-specific and body-specific factors, physiologically-based pharmacokinetic (PBPK) models have become increasingly used to characterize and explore mechanistic insights into drug disposition. Thus, PBPK models can be a bridge between findings from basic science and utilization in predictive science. Pediatric PBPK models incorporate additional system specific information on developmental physiology and ontogeny and have been used to predict pharmacokinetic parameters from preterm neonates onwards. These models have been advocated by regulatory authorities in order to support pediatric clinical trials. The purpose of this chapter is to highlight accumulated knowledge and findings from basic research focusing on P450 enzymes, as well as the current status and future challenges of expanding the utilization of pediatric PBPK modeling.

Development of best practices in physiologically based pharmacokinetic modeling to support clinical pharmacology regulatory decision-making-A workshop summary.

Development of best practices in physiologically based pharmacokinetic modeling to support clinical pharmacology regulatory decision-making-A workshop summary.

Model-Based Drug-Drug Interaction Extrapolation Strategy From Adults to Children: Risdiplam in Pediatric Patients With Spinal Muscular Atrophy.

Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients ≥2 months old. Risdiplam exhibits time‐dependent inhibition of cytochrome P450 (CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug–drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically‐based pharmacokinetic (PBPK) model‐based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11‐fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18‐fold lower in vivo CYP3A inactivation constant compared with the in vitro value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK‐predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months–18 years was negligible (midazolam AUCR of 1.09–1.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model‐based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations.

Population pharmacokinetic analysis of rivaroxaban in children and comparison to prospective physiologically-based pharmacokinetic predictions.

Rivaroxaban has been investigated in the EINSTEIN‐Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan‐procedure. Physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn‐and‐confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN‐Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety‐one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight‐adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN‐Jr phase III study.

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.

Physiologically Based Pharmacokinetic Modeling for Selumetinib to Evaluate Drug-Drug Interactions and Pediatric Dose Regimens.

Selumetinib (ARRY‐142886), an oral, potent and highly selective allosteric mitogen‐activated protein kinase kinase 1/2 inhibitor, is approved by the US Food and Drug Administration for the treatment of pediatric patients aged ≥2 years with neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas. A physiologically based pharmacokinetic (PBPK) model was constructed to predict plasma concentration–time profiles of selumetinib, and to evaluate the impact of coadministering moderate cytochrome P450 (CYP) 3A4/2C19 inhibitors/inducers. The model was also used to extrapolate pharmacokinetic exposures from older children with different body surface area to guide dosing in younger children. This model was built based on physiochemical data and clinical in vivo drug‐drug interaction (DDI) studies with itraconazole and fluconazole, and verified against data from an in vivo rifampicin DDI study and an absolute bioavailability study. The pediatric model was updated by changing system‐specific input parameters using the Simcyp pediatric module. The model captured the observed selumetinib pharmacokinetic profiles and the interactions with CYP inhibitors/inducers. The predictions from the PBPK model showed a DDI effect of 30% to 40% increase or decrease in selumetinib exposure when coadministered with moderate CYP inhibitors or inducers, respectively, which was used to inform dose management and adjustments. The pediatric PBPK model was applied to simulate exposures in specific body surface area brackets that matched those achieved with a 25 mg/m2 dose in SPRINT clinical trials. The pediatric PBPK model was used to guide the dose for younger patients in a planned pediatric clinical study.

A best practice framework for applying physiologically-based pharmacokinetic modeling to pediatric drug development.

Pediatric physiologically‐based pharmacokinetic (PBPK) models have broad application in the drug development process and are being used not only to project doses for clinical trials but increasingly to replace clinical studies. However, the approach has yet to become fully integrated in regulatory submissions. Emerging data support an expanded integration of the PBPK model informed approach in regulatory guidance on pediatrics. Best practice standards are presented for further development through interaction among regulators, industry, and model providers.