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Effect of Cyclosporin A and Impact of Dose Staggering on OATP1B1/1B3 Endogenous Substrates and Drug Probes for Assessing Clinical Drug Interactions
Author(s) -
Mochizuki Tatsuki,
ZamekGliszczynski 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
Publication year - 2022
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.2584
Subject(s) - pitavastatin , pharmacology , rosuvastatin , chemistry , atorvastatin , statin , endogeny , medicine , biochemistry
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 K i ,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.