Quantitative, Translational and ADME Sciences, AbbVie Inc., North Chicago, Illinois, USA.
Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA.
Clin Pharmacol Ther. 2024 Nov;116(5):1334-1342. doi: 10.1002/cpt.3399. Epub 2024 Aug 5.
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) and area under the plasma concentration curve (AUC) by 141% and 55%, respectively when co-administered, whereas atorvastatin C increased by 40% with no effect on its AUC 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]/[OATP1B1 IC] of > 0.1 are associated with > 1.25-fold increase in CP-I C 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.
西地罗格用于治疗慢性斑块状银屑病，是一种视黄酸受体相关孤儿受体γ胸腺的反向激动剂。西地罗格在体外诱导细胞色素 P450（CYP）3A4，同时抑制 P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）、有机阴离子转运多肽（OATP）1B1 和 OATP1B3。静态药物相互作用（DDI）预测提示 CYP3A4 可能发生临床诱导，以及 P-gp、BCRP 和 OATP1B1 的抑制作用，这导致在解释西地罗格与 CYP3A、P-gp、BCRP 和 OATP1B1/3 底物之间的 DDI 研究时存在挑战。在此，研究了健康参与者中西地罗格对两种他汀类药物药代动力学的影响。原卟啉 I（CP-I）是一种选择性的内源性 OATP1B 生物标志物，用于评估西地罗格对 OATP1B 的影响。西地罗格（375mg 每日一次）与瑞舒伐他汀合用使最大血浆浓度（C）和曲线下面积（AUC）分别增加 141%和 55%，而阿托伐他汀 C 增加 40%，与瑞舒伐他汀/阿托伐他汀单独给药相比 AUC 无变化。西地罗格未增加 CP-I 暴露量，表明无临床 OATP1B 抑制作用。西地罗格与瑞舒伐他汀合用使瑞舒伐他汀暴露量增加，阿托伐他汀暴露量变化最小，这归因于 BCRP 抑制以及 P-gp/BCRP 抑制与 CYP3A 诱导之间的相互作用。与两种研究药物（glecaprevir 和 flubentylosin）的数据进行的相关性分析表明，OATP1B1 R 值>1.5 和 [C]/[OATP1B1 IC]>0.1 与 CP-I C 比值增加>1.25 倍相关。这证明了 CP-I 在阐明涉及多种转运体和酶的复杂 DDI 机制方面的实用性，并提出了用于静态 OATP1B 抑制预测的改进标准。
