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Papers by Khaled Abduljalil

Research paper thumbnail of Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models

Drug Metabolism and Disposition, 2022

Concerns over maternal and fetal drug exposures highlights the need for a better understanding of... more Concerns over maternal and fetal drug exposures highlights the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modelling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiological changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared to the observed data. Fully bottom-up feto-placental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in non-pregnant and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed PK data reported in 9 maternal (5 fetoplacental) studies for cefuroxime, 10 maternal (5 fetoplacental) studies for cefazolin, and 6 maternal (2 fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively use for maternal/fetal risk assessment following maternally administered drugs or unintended exposure to environmental toxicants.

Research paper thumbnail of Age Variation when Coining Drugs as High vs Low Hepatic Extraction Ratio

Hepatic extraction ratio (EH) is commonly considered as 'an inherent attribute' of drug. It deter... more Hepatic extraction ratio (EH) is commonly considered as 'an inherent attribute' of drug. It determines the main physiological and biological elements of the system (patient attributes) which are most significant in inter-individual variability of clearance. EH consists of three agedependent parameters: fraction of unbound drug in blood (fuB), hepatic intrinsic clearance of unbound drug (CLuint,H) and hepatic blood flow (QH). When age-effects on these elements are This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward.

Research paper thumbnail of Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Journal of Pharmacokinetics and Pharmacodynamics, 2020

Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the ... more Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

Research paper thumbnail of Assessment of Maternal and Fetal Dolutegravir Exposure by IntegratingEx VivoPlacental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling

Clinical Pharmacology & Therapeutics, 2019

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  Pregnancy is associated with a var... more Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  Pregnancy is associated with a variety of physiological and anatomic changes that can alter maternal antiretroviral pharmacokinetics (PK). Placental transfer of antiretrovirals may cause fetal toxicity or have beneficial effects as antenatal prophylaxis. WHAT QUESTION DID THIS STUDY ADDRESS?  Can fetal exposure to dolutegravir (DTG) be simulated by incorporating ex vivo placental drug transfer data in a pregnancy physiologically-based pharmacokinetic (PBPK) model? WHAT DOES THIS STUDY ADD TO OUR KNOW-LEDGE?  Model simulations adequately captured maternal and fetal DTG exposure during late pregnancy. A dose of 50 mg DTG q.d. was predicted to result in sufficiently high maternal plasma levels during pregnancy to achieve viral suppression and provide fetal prophylaxis. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE?  Simulation of maternal and fetal DTG PK by pregnancy-PBPK modeling is a valuable tool to guide maternal dosing.

Research paper thumbnail of Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population

Clinical Pharmacokinetics, 2019

Background Preterm neonates are usually not part of a traditional drug development programme, how... more Background Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. Objective The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. Methods A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. Results The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. Conclusion While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.

Research paper thumbnail of P85 Prediction of raltegravir plasma concentration in HIV paediatric patients using physiologically-based pharmacokinetic model

Archives of Disease in Childhood, 2019

BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disp... more BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disposition kinetics including the ontogeny of the major metabolic enzyme (UGT1A1) is important in prediction of raltaeravir pharmacokinetics in paediatric patients.MethodsSim-Raltegravir compound file in Simcyp simulator version 18 was used to predict pharmacokinetics in paediatric subjects aged 4 weeks to 6 months, 0.5 to 2, 2 to 6 and 6 to 12 years. Details of trial design were matched as closely as possible with a clinical study.1 Rate of absorption and variability in first order absorption model within Simcyp were set to the reported values. Predicted plasma concentration time profiles with 5th and 95th percentile were compared with observations.ResultsThe predicted vs. observed geometric mean area under plasma concentration-time profile of raltegravir was 18.4 vs. 22.3 µM.h in subjects 4 weeks to 6 months and 16.5 vs. 19.8 µM.h in those 0.5 to 2 years old. In 2 to 6 and 6 to 12 year ol...

Research paper thumbnail of O07 Predictive performance of a physiologically based pharmacokinetic model of caffeine in the preterm population

Archives of Disease in Childhood, 2019

BackgroundCaffeine has been extensively used in the treatment of apnoea in premature infants,1 it... more BackgroundCaffeine has been extensively used in the treatment of apnoea in premature infants,1 its disposition varies with postnatal age2 and can differ markedly between premature and term neonates.MethodsThe Preterm population within the Simcyp Simulator V18R1 population library was used to replicate clinical studies to predict caffeine exposure after single3 and multiple4 intravenous administration to preterm neonates of gestational weeks 28.5 and 29 (28–33) respectively, ranging in postnatal age of 3–30 days and 0–3 days respectively. Predictive performance of the Physiologically Based Pharmacokinetic Model (PBPK) was evaluated by comparing the simulated to the clinical results. A population simulation was performed for the single dose study as only pharmacokinetic parameters were available. However, for multiple doses study, where individual plasma concentration-time profile data were available, simulations were performed for each individual.ResultsPBPK model predictions for caf...

Research paper thumbnail of Drug dosing in pregnant women: Challenges and opportunities in using physiologically-based pharmacokinetic modeling and simulations

CPT: pharmacometrics & systems pharmacology, Jan 19, 2018

The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recogniz... more The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal exposure of drugs are summarized. Future opportunities to use PBPK models to predict breast milk exposure and assess human fetotoxicity risks are presented.

Research paper thumbnail of More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

The Journal of Clinical Pharmacology, 2016

Rosuvastatin is a substrate of choice in clinical studies of organic anion-transporting polypepti... more Rosuvastatin is a substrate of choice in clinical studies of organic anion-transporting polypeptide (OATP)1B1-and OATP1B3-associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability-limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor-transporter and 45 intermediate-transporter individuals are required to achieve 80% power to discriminate the AUC 0-48h of rosuvastatin from that of the extensive-transporter phenotype. This number was reduced to 7 poor-transporter and 40 intermediate-transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design.

Research paper thumbnail of Simulation of virtual human subjects to investigate the impact of

In Fip Pharmaceutical Sciences 2010 World Congress 14 Nov 2010 18 Nov 2010 New Orleans Usa 2010, 2010

We previously developed an approach to investigate the impact of CYP2C9 polymorphisms within a po... more We previously developed an approach to investigate the impact of CYP2C9 polymorphisms within a population2,3, which was also adopted by other investigators4. The objective of this study was to extend this approach using prior in vitro and in vivo information the on metabolism and kinetics of omeprazole in order to evaluate the likely impact of the *17/*17 genotype on the pharmacokinetics (AUC) of omeprazole in a virtual population.

Research paper thumbnail of A Tutorial on Pharmacodynamic Scripting Facility in Simcyp

CPT: pharmacometrics & systems pharmacology, Jan 9, 2016

The Simcyp Simulator provides a framework for mechanistic Physiologically-Based Pharmacokinetic/P... more The Simcyp Simulator provides a framework for mechanistic Physiologically-Based Pharmacokinetic/Pharmacodynamic modelling of potentially interacting drugs. It also provides a scripting facility, using the Lua language, for developing customised pharmacodynamic and toxicity models driven by drug concentrations at the site of action. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Drug Metabolism and Disposition, 2016

The hepatic extraction ratio (E H) is commonly considered an "inherent attribute" of drug. It det... more The hepatic extraction ratio (E H) is commonly considered an "inherent attribute" of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The E H consists of three age-dependent parameters: fraction of unbound drug in blood (f u.B), hepatic intrinsic clearance of unbound drug (CL u.int,H), and hepatic blood flow (Q H). When the age-effects on these elements are not proportional, a given drug may shift from so-called high extraction status to low extraction. To demonstrate the impact of age-related changes on f u.B , CL u. int,H , and Q H , the E H of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CL u.int,H than midazolam were investigated in pediatrics based on known ontogeny functions. The E H was simulated using Simcyp software, version 14. This was then complemented by a comprehensive literature survey to identify the commonly applied covariates in pediatric population pharmacokinetic (PopPK) studies. Midazolam E H decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CL u.int,H and f u. B than in adults and reducing the impact of Q H on clearance. The drug with 10-fold higher CL u.int,H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CL u.int,H remained low extraction from birth to adulthood. Approximately 50% of collected PopPK studies (n = 120) did not consider interaction between age and other covariates. Interaction between covariates and age should be considered as part of studies involving younger pediatric patients. The E H cannot be considered an inherent drug property without considering the effect of age.

Research paper thumbnail of Anatomical and Changes with Gestational Age during normal Pregnancy: A Database for Parameters Required in Physiologically Based Pharmacokinetic Modelling

Clin Pharmacokin 2011, 2011

Research paper thumbnail of Predicting the Effect of CYP2D6 Polymorphism on Pharmacodynamic Response to Metoprolol

Research paper thumbnail of Erratum to: A Re-evaluation and Validation of Ontogeny Functions for Cytochrome P450 1A2 and 3A4 Based on In Vivo Data

Clinical Pharmacokinetics, 2015

Research paper thumbnail of Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmacokinetics of dextromethorphan

Clinical pharmacology and therapeutics, 2010

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2... more The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These ...

Research paper thumbnail of Deciding on success criteria for predictability of pharmacokinetic parameters from in vitro studies: an analysis based on in vivo observations

Drug metabolism and disposition: the biological fate of chemicals, 2014

Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, ... more Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (Vss) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and Vss values obtained from one clinical st...

Research paper thumbnail of Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults

Biopharmaceutics & drug disposition, Jan 19, 2015

Purpose. Gastric emptying (GE) is often reported to be slower and more irregular in premature neo... more Purpose. Gastric emptying (GE) is often reported to be slower and more irregular in premature neonates than in older children and adults. The aim of this study was to investigate the impact of age and other covariates on the rate of GE. Methods. The effect of age on the mean gastric residence times (MGRT) of liquid and solid food was assessed by analysing 49 published studies of 1457 individuals, aged from 28 weeks gestation to adults. The data were modelled using the nonlinear mixed-effects approach within NONMEM version 7.2 (ICON, Dublin, Ireland), with evaluation of postnatal age, gestational age and meal type as covariates. A double Weibull function was selected as a suitable model since it could account for the typical biphasic nature of GE. Results. Age was not a significant covariate for GE but meal type was. Aqueous solutions were associated with the fastest emptying time (mean simulated gastric residence time of 45 min) and solid food was associated with the slowest (98 min...

Research paper thumbnail of Physiologically-Based Pharmacokinetics

Biosimulation in Biomedical Research, Health Care and Drug Development, 2011

... Cytochrome P450 (CYP) 3A and multidrug resistance P-glycoprotein (P-gp; also known as MDR1, A... more ... Cytochrome P450 (CYP) 3A and multidrug resistance P-glycoprotein (P-gp; also known as MDR1, ABCB1) are present at high levels in the villous tip of enterocytes in ... nf ugutCent; n(16.2) dCent; n dt D 1Vent; n  ka; nMdn Q ent; n Cent; n . CLuintg; n C CLuintT; n/fugut Cent; n ...

Research paper thumbnail of Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability

Frontiers in pharmacology, 2014

This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-... more This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to...

Research paper thumbnail of Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models

Drug Metabolism and Disposition, 2022

Concerns over maternal and fetal drug exposures highlights the need for a better understanding of... more Concerns over maternal and fetal drug exposures highlights the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modelling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiological changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared to the observed data. Fully bottom-up feto-placental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in non-pregnant and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed PK data reported in 9 maternal (5 fetoplacental) studies for cefuroxime, 10 maternal (5 fetoplacental) studies for cefazolin, and 6 maternal (2 fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively use for maternal/fetal risk assessment following maternally administered drugs or unintended exposure to environmental toxicants.

Research paper thumbnail of Age Variation when Coining Drugs as High vs Low Hepatic Extraction Ratio

Hepatic extraction ratio (EH) is commonly considered as 'an inherent attribute' of drug. It deter... more Hepatic extraction ratio (EH) is commonly considered as 'an inherent attribute' of drug. It determines the main physiological and biological elements of the system (patient attributes) which are most significant in inter-individual variability of clearance. EH consists of three agedependent parameters: fraction of unbound drug in blood (fuB), hepatic intrinsic clearance of unbound drug (CLuint,H) and hepatic blood flow (QH). When age-effects on these elements are This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward.

Research paper thumbnail of Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Journal of Pharmacokinetics and Pharmacodynamics, 2020

Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the ... more Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

Research paper thumbnail of Assessment of Maternal and Fetal Dolutegravir Exposure by IntegratingEx VivoPlacental Perfusion Data and Physiologically‐Based Pharmacokinetic Modeling

Clinical Pharmacology & Therapeutics, 2019

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  Pregnancy is associated with a var... more Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  Pregnancy is associated with a variety of physiological and anatomic changes that can alter maternal antiretroviral pharmacokinetics (PK). Placental transfer of antiretrovirals may cause fetal toxicity or have beneficial effects as antenatal prophylaxis. WHAT QUESTION DID THIS STUDY ADDRESS?  Can fetal exposure to dolutegravir (DTG) be simulated by incorporating ex vivo placental drug transfer data in a pregnancy physiologically-based pharmacokinetic (PBPK) model? WHAT DOES THIS STUDY ADD TO OUR KNOW-LEDGE?  Model simulations adequately captured maternal and fetal DTG exposure during late pregnancy. A dose of 50 mg DTG q.d. was predicted to result in sufficiently high maternal plasma levels during pregnancy to achieve viral suppression and provide fetal prophylaxis. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE?  Simulation of maternal and fetal DTG PK by pregnancy-PBPK modeling is a valuable tool to guide maternal dosing.

Research paper thumbnail of Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population

Clinical Pharmacokinetics, 2019

Background Preterm neonates are usually not part of a traditional drug development programme, how... more Background Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. Objective The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. Methods A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. Results The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. Conclusion While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.

Research paper thumbnail of P85 Prediction of raltegravir plasma concentration in HIV paediatric patients using physiologically-based pharmacokinetic model

Archives of Disease in Childhood, 2019

BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disp... more BackgroundRaltegravir is a drug used to treat patients with HIV infection. Understanding the disposition kinetics including the ontogeny of the major metabolic enzyme (UGT1A1) is important in prediction of raltaeravir pharmacokinetics in paediatric patients.MethodsSim-Raltegravir compound file in Simcyp simulator version 18 was used to predict pharmacokinetics in paediatric subjects aged 4 weeks to 6 months, 0.5 to 2, 2 to 6 and 6 to 12 years. Details of trial design were matched as closely as possible with a clinical study.1 Rate of absorption and variability in first order absorption model within Simcyp were set to the reported values. Predicted plasma concentration time profiles with 5th and 95th percentile were compared with observations.ResultsThe predicted vs. observed geometric mean area under plasma concentration-time profile of raltegravir was 18.4 vs. 22.3 µM.h in subjects 4 weeks to 6 months and 16.5 vs. 19.8 µM.h in those 0.5 to 2 years old. In 2 to 6 and 6 to 12 year ol...

Research paper thumbnail of O07 Predictive performance of a physiologically based pharmacokinetic model of caffeine in the preterm population

Archives of Disease in Childhood, 2019

BackgroundCaffeine has been extensively used in the treatment of apnoea in premature infants,1 it... more BackgroundCaffeine has been extensively used in the treatment of apnoea in premature infants,1 its disposition varies with postnatal age2 and can differ markedly between premature and term neonates.MethodsThe Preterm population within the Simcyp Simulator V18R1 population library was used to replicate clinical studies to predict caffeine exposure after single3 and multiple4 intravenous administration to preterm neonates of gestational weeks 28.5 and 29 (28–33) respectively, ranging in postnatal age of 3–30 days and 0–3 days respectively. Predictive performance of the Physiologically Based Pharmacokinetic Model (PBPK) was evaluated by comparing the simulated to the clinical results. A population simulation was performed for the single dose study as only pharmacokinetic parameters were available. However, for multiple doses study, where individual plasma concentration-time profile data were available, simulations were performed for each individual.ResultsPBPK model predictions for caf...

Research paper thumbnail of Drug dosing in pregnant women: Challenges and opportunities in using physiologically-based pharmacokinetic modeling and simulations

CPT: pharmacometrics & systems pharmacology, Jan 19, 2018

The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recogniz... more The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal exposure of drugs are summarized. Future opportunities to use PBPK models to predict breast milk exposure and assess human fetotoxicity risks are presented.

Research paper thumbnail of More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

The Journal of Clinical Pharmacology, 2016

Rosuvastatin is a substrate of choice in clinical studies of organic anion-transporting polypepti... more Rosuvastatin is a substrate of choice in clinical studies of organic anion-transporting polypeptide (OATP)1B1-and OATP1B3-associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability-limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor-transporter and 45 intermediate-transporter individuals are required to achieve 80% power to discriminate the AUC 0-48h of rosuvastatin from that of the extensive-transporter phenotype. This number was reduced to 7 poor-transporter and 40 intermediate-transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design.

Research paper thumbnail of Simulation of virtual human subjects to investigate the impact of

In Fip Pharmaceutical Sciences 2010 World Congress 14 Nov 2010 18 Nov 2010 New Orleans Usa 2010, 2010

We previously developed an approach to investigate the impact of CYP2C9 polymorphisms within a po... more We previously developed an approach to investigate the impact of CYP2C9 polymorphisms within a population2,3, which was also adopted by other investigators4. The objective of this study was to extend this approach using prior in vitro and in vivo information the on metabolism and kinetics of omeprazole in order to evaluate the likely impact of the *17/*17 genotype on the pharmacokinetics (AUC) of omeprazole in a virtual population.

Research paper thumbnail of A Tutorial on Pharmacodynamic Scripting Facility in Simcyp

CPT: pharmacometrics & systems pharmacology, Jan 9, 2016

The Simcyp Simulator provides a framework for mechanistic Physiologically-Based Pharmacokinetic/P... more The Simcyp Simulator provides a framework for mechanistic Physiologically-Based Pharmacokinetic/Pharmacodynamic modelling of potentially interacting drugs. It also provides a scripting facility, using the Lua language, for developing customised pharmacodynamic and toxicity models driven by drug concentrations at the site of action. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

Drug Metabolism and Disposition, 2016

The hepatic extraction ratio (E H) is commonly considered an "inherent attribute" of drug. It det... more The hepatic extraction ratio (E H) is commonly considered an "inherent attribute" of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The E H consists of three age-dependent parameters: fraction of unbound drug in blood (f u.B), hepatic intrinsic clearance of unbound drug (CL u.int,H), and hepatic blood flow (Q H). When the age-effects on these elements are not proportional, a given drug may shift from so-called high extraction status to low extraction. To demonstrate the impact of age-related changes on f u.B , CL u. int,H , and Q H , the E H of midazolam and two hypothetical drugs with 10-fold higher and 10-fold lower CL u.int,H than midazolam were investigated in pediatrics based on known ontogeny functions. The E H was simulated using Simcyp software, version 14. This was then complemented by a comprehensive literature survey to identify the commonly applied covariates in pediatric population pharmacokinetic (PopPK) studies. Midazolam E H decreased from 0.6 in adults to 0.02 at birth, making its clearance much more susceptible to changes in CL u.int,H and f u. B than in adults and reducing the impact of Q H on clearance. The drug with 10-fold higher CL u.int,H was categorized as high extraction from 4 days old onward whereas the drug with 10-fold lower CL u.int,H remained low extraction from birth to adulthood. Approximately 50% of collected PopPK studies (n = 120) did not consider interaction between age and other covariates. Interaction between covariates and age should be considered as part of studies involving younger pediatric patients. The E H cannot be considered an inherent drug property without considering the effect of age.

Research paper thumbnail of Anatomical and Changes with Gestational Age during normal Pregnancy: A Database for Parameters Required in Physiologically Based Pharmacokinetic Modelling

Clin Pharmacokin 2011, 2011

Research paper thumbnail of Predicting the Effect of CYP2D6 Polymorphism on Pharmacodynamic Response to Metoprolol

Research paper thumbnail of Erratum to: A Re-evaluation and Validation of Ontogeny Functions for Cytochrome P450 1A2 and 3A4 Based on In Vivo Data

Clinical Pharmacokinetics, 2015

Research paper thumbnail of Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmacokinetics of dextromethorphan

Clinical pharmacology and therapeutics, 2010

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2... more The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These ...

Research paper thumbnail of Deciding on success criteria for predictability of pharmacokinetic parameters from in vitro studies: an analysis based on in vivo observations

Drug metabolism and disposition: the biological fate of chemicals, 2014

Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, ... more Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (Vss) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and Vss values obtained from one clinical st...

Research paper thumbnail of Does age affect gastric emptying time? A model-based meta-analysis of data from premature neonates through to adults

Biopharmaceutics & drug disposition, Jan 19, 2015

Purpose. Gastric emptying (GE) is often reported to be slower and more irregular in premature neo... more Purpose. Gastric emptying (GE) is often reported to be slower and more irregular in premature neonates than in older children and adults. The aim of this study was to investigate the impact of age and other covariates on the rate of GE. Methods. The effect of age on the mean gastric residence times (MGRT) of liquid and solid food was assessed by analysing 49 published studies of 1457 individuals, aged from 28 weeks gestation to adults. The data were modelled using the nonlinear mixed-effects approach within NONMEM version 7.2 (ICON, Dublin, Ireland), with evaluation of postnatal age, gestational age and meal type as covariates. A double Weibull function was selected as a suitable model since it could account for the typical biphasic nature of GE. Results. Age was not a significant covariate for GE but meal type was. Aqueous solutions were associated with the fastest emptying time (mean simulated gastric residence time of 45 min) and solid food was associated with the slowest (98 min...

Research paper thumbnail of Physiologically-Based Pharmacokinetics

Biosimulation in Biomedical Research, Health Care and Drug Development, 2011

... Cytochrome P450 (CYP) 3A and multidrug resistance P-glycoprotein (P-gp; also known as MDR1, A... more ... Cytochrome P450 (CYP) 3A and multidrug resistance P-glycoprotein (P-gp; also known as MDR1, ABCB1) are present at high levels in the villous tip of enterocytes in ... nf ugutCent; n(16.2) dCent; n dt D 1Vent; n  ka; nMdn Q ent; n Cent; n . CLuintg; n C CLuintT; n/fugut Cent; n ...

Research paper thumbnail of Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability

Frontiers in pharmacology, 2014

This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-... more This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to...