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

Kulmatycki, Kenneth, Meyers, Charles, Salunke, Atish Azad, Hanna, Imad, Movva, Aishwarya, Majumdar, Tapan, Natrillo, Adrienne, Vapurcuyan, Arpine, Rebello, Sam, 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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