In Vitro Prediction of Clinical Drug Interactions With CYP3A Substrates: We Are Not There Yet

In 1973, Malcolm Rowland and associates described an approach to predicting clinical pharmacokinetic drug–drug interactions (DDIs) using an inhibition constant determined in vitro (Ki) together with anticipated inhibitor exposure in vivo ([I]). Despite numerous modifications and refinements of the core model over the following 40 years, we still have not achieved a predictive paradigm having accuracy sufficient to justify bypassing all, or even most, clinical DDI studies in the course of drug development.

[1]  M. Solomon,et al.  Ethical Oversight of Learning Health Care Systems , 2013 .

[2]  J. Houston,et al.  The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions , 2006, Journal of Pharmacology and Experimental Therapeutics.

[3]  Tucker Gt,et al.  The rational selection of drug interaction studies: implications of recent advances in drug metabolism. , 1992 .

[4]  J Snoeys,et al.  Evaluation of Various Static In Vitro–In Vivo Extrapolation Models for Risk Assessment of the CYP3A Inhibition Potential of an Investigational Drug , 2014, Clinical pharmacology and therapeutics.

[5]  D. Greenblatt,et al.  Sources of variability in ketoconazole inhibition of human cytochrome P450 3A in vitro , 2010, Xenobiotica; the fate of foreign compounds in biological systems.

[6]  S. Morris,et al.  The PCAST Report: Impact and Implications for the Pharmaceutical Industry , 2013, Clinical pharmacology and therapeutics.

[7]  R B D'Agostino,et al.  A Proposal for Integrated Efficacy-to-Effectiveness (E2E) Clinical Trials , 2013, Clinical pharmacology and therapeutics.

[8]  D. Greenblatt,et al.  In Vitro Prediction of the Terfenadine‐Ketoconazole Pharmacokinetic Interaction , 1994, Journal of clinical pharmacology.

[9]  L. Zhang,et al.  Evaluation of Various Static and Dynamic Modeling Methods to Predict Clinical CYP3A Induction Using In Vitro CYP3A4 mRNA Induction Data , 2014, Clinical pharmacology and therapeutics.

[10]  A. Sjoerdsma,et al.  Eflornithine for African sleeping sickness , 1999, The Lancet.

[11]  T. Spector,et al.  Glucuronidation of 3'-azido-3'-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase. Significance of nucleoside hydrophobicity and inhibition by xenobiotics. , 1991, Biochemical pharmacology.

[12]  Malcolm Rowland,et al.  Kinetics of drug-drug interactions , 1973, Journal of Pharmacokinetics and Biopharmaceutics.

[13]  R. Califf,et al.  Impediments to Clinical Research in the United States , 2012, Clinical pharmacology and therapeutics.

[14]  D. Greenblatt,et al.  Clinical Drug Interactions Due to Metabolic Inhibition: Prediction, Assessment, and Interpretation , 2010 .

[15]  G. Tucker.  The rational selection of drug interaction studies: implications of recent advances in drug metabolism. , 1992, International journal of clinical pharmacology, therapy, and toxicology.

[16]  Anthony J. Sinskey,et al.  Trends in the globalization of clinical trials , 2008, Nature Reviews Drug Discovery.

[17]  D. Greenblatt,et al.  Clinical Studies of Drug–Drug Interactions: Design and Interpretation , 2010 .