Abstract
Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.109.027029.
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ABBREVIATIONS: NME, new molecular entity; P450, cytochrome P450; DDI, drug-drug interaction; RIF, rifampicin; PhRMA, Pharmaceutical Research and Manufacturers of America; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; UGT, uridine diphosphate glucuronosyl transferase; FXR, farnesyl X receptor; PPAR, peroxisome proliferator-activated receptor; VDR, vitamin D receptor; Nrf2, nuclear factor erythroid 2-related factor 2; LBD, ligand binding domain; hPXR, human PXR; SR12813, tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate; SAR, structure-activity relationship; EC50, concentration to reach half the maximal induction effect; bp, base pair; %Act, percentage of activation; [Ind], inducer concentration; Emax, maximal in vitro induction effect; Emin, background level of catalytic activity; AUC, area under the curve; TCDD, 2,3,7,8-tetrachlorobenzo-p-dioxin; 3-MC, 3-methylcholanthrene; BNF, β-naphthoflavone; CITCO, (6-(4-chlorophenyl)imidazo[2,1-β][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime); ITS, insulin, transferrin, and selenium as supplements in hepatocyte culture medium; DMSO, dimethyl sulfoxide; MDR-1, multidrug resistance-1 gene encoding P-glycoprotein expression; IVIVC, in vitro-in vivo correlation; MTT, 3-[4,4-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide3-[4,4-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; fu, fraction unbound in blood (plasma); CLint, intrinsic clearance; RIS, relative induction score; F2, concentration of inducer leading to a 2-fold increase of CYP3A4 mRNA in hepatocytes in vitro; NOEL, no observed effect level.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material. - Accepted April 17, 2009.
- Received February 2, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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