title: Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper.
abstract: 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.
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Rahway, New Jersey, USA. Raymond_Evers@merck.com
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.forename: Shannon
authors.initials: S
authors.lastname: Dallas
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Dickmann
authors.forename: Odette A
authors.initials: OA
authors.lastname: Fahmi
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
authors.forename: Theresa
authors.initials: T
authors.lastname: Nguyen
authors.forename: Aarti H
authors.initials: AH
authors.lastname: Patel
authors.forename: J Greg
authors.initials: JG
authors.lastname: Slatter
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004345:Drug Industry; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D011506:Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D011506:Proteins; D003577:Cytochrome P-450 Enzyme System