Impact of physiologically based pharmacokinetic modeling and simulation in drug development.

Physiologically based pharmacokinetic modeling and simulation can be used to predict the pharmacokinetics of drugs in human populations and to explore the effects of varying physiologic parameters that result from aging, ethnicity, or disease. In addition, the effects of concomitant medications on drug exposure can be investigated; prediction of the magnitude of drug interactions can impact regulatory communications or internal decision-making regarding the requirement for a clinical drug interaction study. Modeling and simulation can also help to inform the design and timings of clinical drug interaction studies, resulting in more efficient use of limited resources and improved planning in addition to promoting mechanistic understanding of observed drug interactions. These approaches have been used in GlaxoSmithKline from drug discovery to registration and have been applied to 41 drugs from a number of therapeutic areas. This report highlights the variety of questions that can be addressed by prospective or retrospective application of modeling and simulation and the impact this can have on clinical drug development (from candidate selection through clinical development to regulatory submissions).

Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper.

Drug-drug interactions (DDIs) between therapeutic proteins (TPs) and small-molecule drugs have recently drawn the attention of regulatory agencies, the pharmaceutical industry, and academia. TP-DDIs are mainly caused by proinflammatory cytokine or cytokine modulator-mediated effects on the expression of cytochrome P450 enzymes. To build consensus among industry and regulatory agencies on expectations and challenges in this area, a working group was initiated to review the preclinical state of the art. This white paper represents the observations and recommendations of the working group on the value of in vitro human hepatocyte studies for the prediction of clinical TP-DDI. The white paper was developed following a "Workshop on Recent Advances in the Investigation of Therapeutic Protein Drug-Drug Interactions: Preclinical and Clinical Approaches" held at the Food and Drug Administration White Oak Conference Center on June 4 and 5, 2012. Results of a workshop poll, cross-laboratory data comparisons, and the overall recommendations of the in vitro working group are presented herein. The working group observed that evaluation of TP-DDI for anticytokine monoclonal antibodies is currently best accomplished with a clinical study in patients with inflammatory disease. Treatment-induced changes in appropriate biomarkers in phase 2 and 3 studies may indicate the potential for a clinically measurable treatment effect on cytochrome P450 enzymes. Cytokine-mediated DDIs observed with anti-inflammatory TPs cannot currently be predicted using in vitro data. Future success in predicting clinical TP-DDIs will require an understanding of disease biology, physiologically relevant in vitro systems, and more examples of well conducted clinical TP-DDI trials.