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Cytochrome P450 3A Induction Predicts P‐glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine
Author(s) -
Lutz Justin D.,
Kirby Brian J.,
Wang Lu,
Song Qinghua,
Ling John,
Massetto Benedetta,
Worth Angela,
Kearney Brian P.,
Mathias Anita
Publication year - 2018
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1072
Subject(s) - pregnane x receptor , carbamazepine , rifabutin , pharmacology , cyp3a , cyp3a4 , p glycoprotein , drug interaction , cyp2b6 , chemistry , cyp2c9 , sofosbuvir , pharmacokinetic interaction , cyp2c19 , cytochrome p450 , pharmacokinetics , medicine , biochemistry , nuclear receptor , metabolism , clarithromycin , antibiotics , multiple drug resistance , epilepsy , genotype , psychiatry , transcription factor , ribavirin , gene
Rifampin demonstrated dose‐dependent relative induction between cytochrome P (CYP)3A and P‐glycoprotein (P‐gp), organic anion transporting polypeptides (OATPs), or CYP2C9; P‐gp, OATP, and CYP2C9 induction was one drug–drug interaction (DDI) category lower than that observed for CYP3A across a wide range of pregnane X receptor (PXR) agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P‐gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six‐probe drug cassette before and after 300 mg q.d. rifabutin or 300 mg b.i.d. carbamazepine. Induction of P‐gp, CYP2C9, and decreased sofosbuvir exposure were successfully predicted by observed CYP3A induction. Carbamazepine induction of OATP was underpredicted, likely due to reported additional non‐PXR agonism. The results demonstrate that the effect of a PXR agonist on CYP3A can be leveraged to inform on induction liability for other primarily PXR‐regulated P450s/transporters, allowing for prioritization of targeted DDI assessments during new drug development.