Coproporphyrin-I as a Selective OATP1B Biomarker Can Be Used to Delineate the Mechanisms of Complex Drug-Drug Interactions: Cedirogant Case Study.

Autor: Kikuchi R; Quantitative, Translational and ADME Sciences, AbbVie Inc., North Chicago, Illinois, USA., Qian Y; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA., Badawi M; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA., Savaryn JP; Quantitative, Translational and ADME Sciences, AbbVie Inc., North Chicago, Illinois, USA., Gannu S; Quantitative, Translational and ADME Sciences, AbbVie Inc., North Chicago, Illinois, USA., Eldred A; Immunology Development, AbbVie Inc., North Chicago, Illinois, USA., Hao S; Discovery and Exploratory Statistics, AbbVie Inc., North Chicago, Illinois, USA., Salem AH; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA.; Clinical Pharmacy, Ain Shams University, Cairo, Egypt., Liu W; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA., Klein CE; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA., Mohamed MF; Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 Nov; Vol. 116 (5), pp. 1334-1342. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1002/cpt.3399
Abstrakt: Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug-drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P-gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P-gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin-I (CP-I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (C max ) and area under the plasma concentration curve (AUC tau ) by 141% and 55%, respectively when co-administered, whereas atorvastatin C max increased by 40% with no effect on its AUC tau compared with administration of rosuvastatin/atorvastatin alone. Cedirogant did not increase CP-I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co-administration of cedirogant is attributed to BCRP inhibition and interplay between P-gp/BCRP inhibition and CYP3A induction, respectively. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [C max,u ]/[OATP1B1 IC 50 ] of > 0.1 are associated with > 1.25-fold increase in CP-I C max ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions.
(© 2024 AbbVie Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
Externí odkaz: