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Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor

Kulmatycki, Kenneth and Meyers, Charles and Salunke, Atish Azad and Hanna, Imad and Movva, Aishwarya and Majumdar, Tapan and Natrillo, Adrienne and Vapurcuyan, Arpine and Rebello, Sam and Sunkara, Gangadhar and Chen, Jin (2015) Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. International Journal of Clinical Pharmacology and Therapeutics, 53 (5). pp. 345-355. ISSN 0946-1965


Objective: An in vitro drug-drug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. Methods: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Results: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC<inf>50</inf> value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentration-dependent manner with estimated IC<inf>50</inf> values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC<inf>τ,ss</inf> of rosuvastatin was unchanged and its C<inf>max,ss</inf> decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC<inf>τ,ss</inf> and C<inf>max,ss</inf> were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. Conclusion: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

Item Type: Article
Keywords: BCRP DGAT-1 Drug-drug interaction OATP Pharmacokinetics Pradigastat Rosuvastatin
Date Deposited: 14 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45


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