Pitavastatin is a more sensitive and selective organic anion‐transporting polypeptide 1B clinical probe than rosuvastatin

Abstract

Aims Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion‐transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. Methods The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. Results Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration–time curve were 5.7‐ and 7.6‐fold for pitavastatin and 4.4‐ and 3.3‐fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. Conclusions The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

“…By contrast, if an inhibitor is also a substrate of OATPs (that can act as a competitive inhibitor), the inhibitor concentration in plasma and in the liver will be increased and decreased, respectively, and that may increase the magnitude of OATP1B1 inhibition in Japanese. The effect of rifampicin (given as a single oral dose, 600 mg) was also examined for pitavastatin in the United States, although the ethnicity of the subjects was not reported (Prueksaritanont et al, 2014). The AUCR of pitavastatin was 5.2, which is similar to that in our study (5.1); however, the C max (10 mg/ml) of rifampicin is lower than that in our study (24 mg/ml) in Japanese.…”

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition

“…A single oral dose of 600-mg rifampin greatly increased the AUCs of pitavastatin (Chen et al, 2013, Prueksaritanont et al, 2014, Prueksaritanont et al, 2017, Takehara et al, 2018, rosuvastatin (Prueksaritanont et al, 2014, Prueksaritanont et al, 2017, Wu et al, 2017, Takehara et al, 2018 and atorvastatin (Lau et al, 2007, He et al, 2009, Maeda et al, 2011, Prueksaritanont et al, 2017, Takehara et al, 2018) by 2.8-to 6.7-fold, 3.0-to 4.7-fold, and 4.6-to 12.0-fold, respectively, in multiple clinical DDI studies. In agreement, the administration of 600-mg rifampin in this study resulted in a 2.8-to 3.7-fold elevation in CPI AUC(0-24h) and a 2.…”

“…Coadministration of pravastatin with diltiazem (120 mg twice a day) did not affect the oral AUC and Cmax of pravastatin, indicating no clinical OATP1B inhibition potential (Azie et al, 1998 The mechanistic static model approach would predict no pharmacokinetic interaction at the liver inlet and plasma concentrations attained because the overall estimated R-value is low (< 1.17) ( shown to have no influence on AUC of pitavastatin (Nakagawa et al, 2013, Prueksaritanont et al, 2017. Pitavastatin is a more sensitive and selective OATP1B clinical probe than rosuvastatin due to lack of complications from drug metabolizing enzymes and gut efflux transporters (Prueksaritanont et al, 2014). It is worth noting that the administration of itraconazole resulted in a 1.8-and 5.6-fold increases in AUC of rosuvastatin and atorvastatin, respectively, in the same subjects.…”

“…b Plasma unbound fraction of inhibitors (Templeton et al, 2008, Prueksaritanont et al, 2014, Prueksaritanont et al, 2017 and Goodman & Gilman 10th Edition, 2001. c Concentrations required to inhibit OATP1B-mediated transport by 50% using statins and estradiol 17β glucuronide (Yoshida et al, 2012, Shen et al, 2013, Nakakariya et al, 2016, Vermeer et al, 2016.…”

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

“…Therefore, in developing new drugs, we have focused on transporter-mediated DDIs. Among transporters, OATPs are involved in the hepatic uptake of various kinds of anionic drugs, such as HMG-CoA reductase inhibitors (Hirano et al, 2004;Kitamura et al, 2008) and angiotensin II receptor antagonists (Nakagomi-Hagihara et al, 2006;Yamashiro et al, 2006), and they affect the pharmacokinetics of their substrates (Yoshida et al, 2012;Prueksaritanont et al, 2014). Significant DDIs mediated by OATPs have been reported in coadministration of inhibitors, such as rifampicin and cyclosporin A, and many of their substrates, such as pravastatin, atorvastatin, and repaglinide (Kajosaari et al, 2005;Lau et al, 2007;Maeda et al, 2011).…”