Cytochrome P450 3A Induction Predicts P‐glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin

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  • Justin D. Lutz
    Department of Clinical Pharmacology Gilead Sciences, Inc. Foster City California USA
  • Brian J. Kirby
    Department of Clinical Pharmacology Gilead Sciences, Inc. Foster City California USA
  • Lu Wang
    Department of Biometrics Gilead Sciences, Inc. Foster City California USA
  • Qinghua Song
    Department of Biometrics Gilead Sciences, Inc. Foster City California USA
  • John Ling
    Department of Clinical Pharmacology Gilead Sciences, Inc. Foster City California USA
  • Benedetta Massetto
    Department of Clinical Operations Gilead Sciences, Inc. Foster City California USA
  • Angela Worth
    Department of Clinical Research Gilead Sciences, Inc. Foster City California USA
  • Brian P. Kearney
    Department of Clinical Pharmacology Gilead Sciences, Inc. Foster City California USA
  • Anita Mathias
    Department of Clinical Pharmacology Gilead Sciences, Inc. Foster City California USA

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<jats:p>Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and, hence, an inducer should induce both, although the magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P‐glycoprotein (P‐gp), organic anion transporting polypeptide (OATP), and breast cancer resistance protein (BCRP)) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical pregnane xenobiotic receptor (PXR) agonist, rifampin, to elicit weak, moderate, and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin, and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg q.d. Unlike CYP3A, only moderate induction of P‐gp, OATP, and CYP2C9 was observed and dose‐dependent induction of P‐gp, OATP, and CYP2C9 was always one drug–drug interaction category lower than observed for CYP3A, even when correcting for probe drug sensitivity. Data from this study establish proof‐of‐concept that P450 induction data can be leveraged to inform on the effect on transporters.</jats:p>

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