PBPK modeling and simulation in drug research and development

Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

[1]  S-M Huang,et al.  Regulatory Experience With Physiologically Based Pharmacokinetic Modeling for Pediatric Drug Trials , 2012, Clinical pharmacology and therapeutics.

[2]  Efthymios Manolis,et al.  Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. , 2009, British journal of clinical pharmacology.

[3]  Xiaomei Zhuang,et al.  Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction , 2014, Biopharmaceutics & drug disposition.

[4]  Guideline on the Investigation of Drug Interactions , 2010 .

[5]  N Parrott,et al.  Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective , 2015, Clinical pharmacology and therapeutics.

[6]  Sheila Annie Peters,et al.  Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models , 2016, Clinical Pharmacokinetics.

[7]  Shiew-Mei Huang,et al.  Evaluation of Exposure Change of Nonrenally Eliminated Drugs in Patients With Chronic Kidney Disease Using Physiologically Based Pharmacokinetic Modeling and Simulation , 2012, Journal of clinical pharmacology.

[8]  Kuresh Youdim,et al.  Application of PBPK modelling in drug discovery and development at Pfizer , 2012, Xenobiotica; the fate of foreign compounds in biological systems.

[9]  Chuang Lu,et al.  Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies , 2013, Drug Metabolism and Disposition.

[10]  K. Venkatakrishnan,et al.  Physiologically based and population PK modeling in optimizing drug development: A predict–learn–confirm analysis , 2015, Clinical pharmacology and therapeutics.

[11]  Torsten Teorell,et al.  Kinetics of distribution of substances administered to the body, II : The intravascular modes of administration , 1937 .

[12]  K. Rowland Yeo,et al.  Prediction of drug clearance in a smoking population: modeling the impact of variable cigarette consumption on the induction of CYP1A2 , 2012, European Journal of Clinical Pharmacology.

[13]  Lei Zhang,et al.  Predicting the Effect of Cytochrome P450 Inhibitors on Substrate Drugs: Analysis of Physiologically Based Pharmacokinetic Modeling Submissions to the US Food and Drug Administration , 2014, Clinical Pharmacokinetics.

[14]  Shiew-Mei Huang,et al.  Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study , 2009, Journal of clinical pharmacology.

[15]  Jon Brumbaugh,et al.  DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION , 2000 .

[16]  Melvin E. Andersen,et al.  Physiologically Based Pharmacokinetic Modeling : Science and Applications , 2005 .

[17]  M Rowland,et al.  Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions , 2012, Clinical pharmacology and therapeutics.

[18]  Vikram Sinha,et al.  Predicting the Effect of CYP3A Inducers on the Pharmacokinetics of Substrate Drugs Using Physiologically Based Pharmacokinetic (PBPK) Modeling: An Analysis of PBPK Submissions to the US FDA , 2016, Clinical Pharmacokinetics.

[19]  Thuy Tran,et al.  Impact of Physiologically Based Pharmacokinetic Modeling and Simulation in Drug Development , 2013, Drug Metabolism and Disposition.

[20]  I Zineh,et al.  Physiologically Based Pharmacokinetic Modeling: From Regulatory Science to Regulatory Policy , 2014, Clinical pharmacology and therapeutics.

[21]  Chuang Lu,et al.  Assessment of cytochrome P450‐mediated drug–drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation , 2014, Biopharmaceutics & drug disposition.

[22]  Chuang Lu,et al.  Comparison of Intrinsic Clearance in Liver Microsomes and Hepatocytes from Rats and Humans: Evaluation of Free Fraction and Uptake in Hepatocytes , 2006, Drug Metabolism and Disposition.

[23]  Lukas Furst,et al.  Physiologically Based Pharmacokinetic Modeling Science And Applications , 2016 .

[24]  Shiew-Mei Huang,et al.  PBPK as a tool in regulatory review. , 2012, Biopharmaceutics & drug disposition.

[25]  Hugues Dolgos,et al.  Physiologically based pharmacokinetic (PBPK) modeling and simulation: applications in lead optimization. , 2009, Current opinion in drug discovery & development.

[26]  Shiew-Mei Huang,et al.  Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK , 2015, CPT: pharmacometrics & systems pharmacology.

[27]  I Zineh,et al.  PBPK Model Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of Drugs That Undergo Multiple Clearance Pathways , 2014, Clinical pharmacology and therapeutics.

[28]  Malcolm Rowland,et al.  Physiologically-based pharmacokinetics in drug development and regulatory science. , 2011, Annual review of pharmacology and toxicology.

[29]  Guidance for Industry Drug Interaction Studies — Study Design , Data Analysis , Implications for Dosing , and Labeling Recommendations , 2022 .

[30]  Thomas Singer,et al.  Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants , 2011, Clinical pharmacokinetics.

[31]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[32]  Y. Sugiyama,et al.  Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver , 2013, Clinical pharmacology and therapeutics.