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Program of physiologically-based pharmacokinetic and pharmacodynamic modeling (PBPK Program)

On August 31, 2018, FDA issued the “Physiologically Based Pharmacokinetic Analyses — Format and Content” final guidance to provide recommendations for sponsors and applicants on the format and content of physiologically based pharmacokinetic (PBPK) analyses submitted to FDA to support applications including, but not limited to, investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs), or abbreviated new drug applications (ANDAs).

Physiologically-based pharmacokinetic models integrate drug (substance) AND system (physiology) information into a mathematical modeling framework. For decades these models were used mainly in the field of toxicology for the prediction of human and animal exposures to environmental toxin. Advancements in computation and medical sciences have fueled the increased use of PBPK models in drug development. These models can be iteratively modified and updated when new knowledge in drug and physiology become available. Through “predict-learn-confirm” cycles, one can not only use these models to describe the clinical observations, but more importantly to predict, via simulations, the untested clinical outcomes. PBPK models have been used by drug developers to predict and evaluate the effect of various intrinsic and extrinsic patient factors, alone or in combination, on the exposure of investigational drugs to support decision on whether, when and how to conduct a clinical pharmacology study. The PBPK program of the Division of Pharmacometrics at FDA has the following missions:

  1. Review the adequacy of submitted PBPK models by drug developers in their ability to support intended purposes at different stages of drug development
  2. Facilitate IND and NDA review process through de novo analyses
  3. Support regulatory policy through scientific research and maintenance of a PBPK knowledgebase
  4. Harmonize regulatory recommendations on the use of PBPK with non-US regulatory body and reach out to scientific community to advance the science of PBPK

PBPK Publications

Topic Publication

Concept, perspective, and best practice

Huang S-M, Rowland M, Application of Physiologically-based pharmacokinetics Modeling in Regulatory Review, Clin Pharmacol Ther, 2012

Huang SM. PBPK as a tool in regulatory review. Biopharm Drug Dispos. 2012

Zhao P, Rowland M, Huang S-M, Best practice in the use of physiologically based pharmacokinetic modeling and simulation to address clinical pharmacology regulatory questions. Clin Pharmacol Ther, 2012

Zhao P, Zhang L, Grillo JA, et al, Application of Physiologically-based pharmacokinetics (PBPK) Modeling and Simulation During Regulatory Science. Clin Pharmacol Ther, 2011
Huang SM, Abernethy DR, Wang Y, et al. The utility of modeling and
simulation in drug development and regulatory review. J Pharm Sci. 2013

Study design

Duan JZ, Jackson AJ, Zhao P. Bioavailability Considerations in Evaluating Drug-Drug Interactions Using the Population Pharmacokinetic Approach. J Clin Pharmacol. 2011

Zhao P, Ragueneau-Majlessi I, Zhang L, et al. Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study. J Clin Pharmacol. 2009

Organ impairment

Grillo JA, Zhao P, Bullock J, et al, Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice, Biopharm Drug Dispo, 2012

Zhao P, de LT Vierira M, Grillo J, et al, Evaluation of Exposure Change of Non-renally Eliminated Drugs in Patients with Chronic Kidney Disease Using Physiologically-based Pharmacokinetic Modeling and Simulation.  J Clin Pharmacol, 2012

Non-linear PK, DDI prediction

De LT Vieira M, Zhao P, Gil Berglund E, et al, Predicting Drug Interaction Potential by Using a Physiologically-based pharmacokinetics (PBPK) Model: Case Study of Telithromycin, a Time-Dependent CYP3A inhibitor. Clin Pharmacol Ther, 2012

Pediatrics

Leong R, Vieira ML, Zhao P, et al. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther 2012

Pregnancy

Ke AB, Nallani S, Zhao P, et al. A PBPK Model to Predict Disposition of CYP3A-metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction. Clin Pharmcol Ther: Pharmacometrics & Systems Pharmacology, 2012

Ke AB, Nallani SC, Zhao P, Rostami-Hodjegan A, Isoherranen N, Unadkat JD. A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women. Drug Metab Dispos. 41:801-13. 2013

 

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