Effects of Rifampicin on the Pharmacokinetics and Safety of Carotegrast Methyl in Healthy Subjects: A Randomized 2 x 2 Crossover Study

Aims: To evaluate the effect of the combination of carotegrast methyl with rifampicin, a potent inhibitor of organic anion transporter polypeptide, on the pharmacokinetics (PK), safety and tolerability. Methods: In this 2 x 2 crossover study in 20 healthy Japanese adults, 10 subjects received carotegrast methyl 960 mg and rifampicin 600 mg on day 1, and received carotegrast methyl 960 mg on day 8. The subjects in the other sequence received the same treatments but in the opposite order. When the 90% confidence interval (CI) of the geometric mean ratio of the AUC 0-t and C max for carotegrast, the main active metabolite of carotegrast methyl, with/without rifampicin fell within the range of 0.80 – 1.25, it was deemed that no PK interaction occurred. Adverse events (AEs) were monitored. Results: The C max and AUC 0-t for carotegrast with/without rifampicin was 11724.5 ± 6097.6 vs 2620.1 ± 1843.0 ng mL -1 , and 55046.0 ± 23427.8 vs 9849.9 ± 4580.6 ng h mL -1 , respectively. The ratios (90% CI) of the C max and AUC 0-t with/without rifampicin were 4.78 (3.64 – 6.29) and 5.59 (4.60 – 6.79), respectively, indicating carotegrast has a PK interaction with rifampicin. The combination with rifampicin also increased the exposure of carotegrast and its metabolites. The incidence of any AEs with/without rifampicin was five (25.0%) and one (5.0%), respectively. Conclusion: Coadministration of carotegrast methyl with rifampicin significantly increased exposure of carotegrast compared with carotegrast methyl administration alone. However, no increase in the incidence of adverse drug reactions due to coadministration with rifampicin was observed.