Abstract

Objective: An in vitro drugdrug 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 × 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 IC₅₀ value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC₅₀ 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_τ,ss of rosuvastatin was unchanged and its C_max,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC_τ,ss and C_max,ss 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.

Author Details

Authors

• Kenneth Kulmatycki¹
• Imad Hanna²
• Dan Meyers¹
• Atish Salunke³
• Aishwarya Movva¹
• Tapan Majumdar²
• Adrienne Natrillo²
• Arpine Vapurcuyan²
• Sam Rebello²
• Gangadhar Sunkara²
• Jin Chen²

Departments

• ¹ Novartis Institutes for BioMedical Research, Cambridge, MA,
• ² Novartis Institutes for BioMedical Research, East Hanover, NJ, USA, and
• ³ Novartis Institutes for BioMedical Research, Hyderabad, India

Address

Kenneth Kulmatycki, PhD
Novartis Institutes for BioMedical Research, Inc.
200 Technology Square
Cambridge, MA 02139, USA
Email: [email protected]

Citation