In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the Cmax , AUC and terminal elimination half-life of alisporivir by approximately two-, eight- ,and threefold, respectively. Co-administration with azithromycin (a putative weak CYP3A4 inhibitor and substrate) had no impact on the Cmax and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir Cmax and AUC and a fourfold reduction in alisporivir terminal elimination half-life. Alisporivir as an inhibitor of CYP3A4 caused a 39% increase in azithromycin exposure. The results from these studies establish alisporivir as a sensitive CYP3A4 substrate in vivo. Consequently, co-administered potent CYP3A4 inhibitors and inducers are likely to cause clinically significant changes in the exposure to alisporivir.
The effect of telbivudine on cardiac repolarization was evaluated in healthy participants at clinical and supratherapeutic doses. Sixty-two participants were enrolled, stratified by sex, and randomized according to a crossover design among 4 treatment sequences: placebo, a single moxifloxacin 400-mg dose as positive calibrator, and telbivudine 600 and 1800 mg/d for 7 days. Intensive time-matched electrocardiogram measurements and pharmacokinetic sampling were performed at baseline and on day 7 over 24 hours. For telbivudine and moxifloxacin, time-matched, placebo-adjusted change from baseline in QT was calculated and corrected using Fridericia's formula (QTcF). While moxifloxacin produced the expected significant changes in QTcF, none of the changes in QTcF for either doses of telbivudine exceeded 5 ms, and none of the associated upper 1-sided 95% confidence intervals (CI) exceeded the limit of 10 ms. There was no increase in QTcF with increasing plasma telbivudine. The supratherapeutic dose of telbivudine was well tolerated with a safety profile similar to the clinical dose despite a 3-fold increase in plasma exposure. This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin.
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