Effect of Cyclosporin A and Impact of Dose Staggering on OATP1B1/1B3 Endogenous Substrates and Drug Probes for Assessing Clinical Drug Interactions. Issue 6 (11th April 2022)

• Record Type: Journal Article
• Authors: Mochizuki, Tatsuki; Zamek‐Gliszczynski, Maciej J.; Yoshida, Kenta; Mao, Jialin; Taskar, Kunal; Hirabayashi, Hideki; Chu, Xiaoyan; Lai, Yurong; Takashima, Tadayuki; Rockich, Kevin; Yamaura, Yoshiyuki; Fujiwara, Kaku; Mizuno, Tadahaya; Maeda, Kazuya; Furihata, Kenichi; Sugiyama, Yuichi; Kusuhara, Hiroyuki
• Is Part Of: Clinical pharmacology & therapeutics. Volume 111:Issue 6(2022)
• Page Start: 1315
• Page End: 1323
• Publication Date: 2022-04-11
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.2584
• Languages: English
• ISSNs: 0009-9236

Abstract

Abstract : This study was designed to assess the quantitative performance of endogenous biomarkers for organic anion transporting polypeptide (OATP) 1B1/1B3‐mediated drug‐drug interactions (DDIs). Ten healthy volunteers orally received OATP1B1/1B3 probe cocktail (0.2 mg pitavastatin, 1 mg rosuvastatin, and 2 mg valsartan) and an oral dose of cyclosporin A (CysA, 20 mg and 75 mg) separated by a 1‐hour interval (20 mg (−1 hour), and 75 mg (−1 hour)). CysA 75 mg was also given with a 3‐hour interval (75 mg (−3 hours)) to examine the persistence of OATP1B1/1B3 inhibition. The area under the plasma concentration‐time curve ratios (AUCRs) were 1.63, 3.46, and 2.38 (pitavastatin), 1.39, 2.16, and 1.81 (rosuvastatin), and 1.42, 1.77, and 1.85 (valsartan), at 20 mg, 75 mg (−1 hour) and 75 mg (−3 hours) of CysA, respectively. CysA effect on OATP1B1/1B3 was unlikely to persist at the dose examined. Among 26 putative OATP1B1/1B3 biomarkers evaluated, AUCR and maximum concentration ratio ( C max R) of CP‐I showed the highest Pearson's correlation coefficient with CysA AUC (0.94 and 0.93, respectively). Correlation between AUCR of pitavastatin, and C max R or AUCR of CP‐I were consistent between this study and our previous study using rifampicin as an OATP1B1/1B3 inhibitor. Nonlinear regression analysis of AUCR −1 of pitavastatin and CP‐I against CysA C max yielded K i, OATP1B1/1B3, app (109 ± 35 and 176 ± 42 nM, respectively), similar to the Ki, OATP1B1/1B3 estimated by our physiologically‐based pharmacokinetic model analysis described previously (107 nM). The endogenous OATP1B1/1B3 biomarkers, particularly C max R and AUCR of CP‐I, corroborates OATP1B1/1B3 inhibition and yields valuable information that improve accurate DDI predictions in drug development, and enhance our understanding of interindividual variability in the magnitude of DDIs.