Drug-drug interaction study of ACT-178882, a new renin inhibitor, and diltiazem in healthy subjects.

The cytochrome P450 (CYP) enzyme, CYP3A4, metabolizes ACT-178882, a new direct renin inhibitor. This study investigated the effect of diltiazem, a moderate inhibitor of CYP3A4, on the single-dose pharmacokinetics of ACT-178882 in healthy subjects. In this open-label, two-way crossover, drug-drug interaction study, healthy young male subjects received treatments A and B in a randomized fashion. Treatment A consisted of a single dose of 100 mg ACT-178882 and treatment B of diltiazem 300 mg once a day for 13 days and a single dose of 100 mg ACT-178882 on day 4. Serial blood samples for the measurement of ACT-178882 were drawn pre-dose and up to 120 h post-dose during treatment A and pre-dose ACT-178882 and up to 240 h post-dose during treatment B. Trough blood samples for the measurement of diltiazem were taken on days 1-5 of dosing during treatment B. Safety was assessed by recording of vital signs and electrocardiogram, clinical laboratory tests and adverse event reporting. Fourteen subjects were enrolled and completed the study. In the absence of diltiazem, the mean (95 % confidence interval [CI]) maximum concentration (Cmax) and area under the curve from time zero to infinity (AUC∞) were 26.8 (20.1-35.8) ng/mL and 454 (351-587) ng·h/mL, respectively. In the presence of diltiazem these values were 43.5 (36.8-51.4) ng/mL and 918 (781-1078) ng·h/mL, respectively. The median time to Cmax (tmax) for ACT-178882 was prolonged from 3.5 to 5.0 h by diltiazem whereas its apparent terminal half-life (t½) was unaffected by diltiazem, 22.9 and 24.2 h for treatments A and B, respectively. Using treatment A as reference, the geometric mean ratio (90 % CI) was 1.62 (1.36-1.94) for Cmax and 2.02 (1.75-2.34) for AUC∞, indicating a significant interaction between ACT-178882 and diltiazem. One (7.1 %) and 3 (21.3 %) of 14 subjects reported an adverse event during treatment A and B, respectively, with headache being the most frequently reported, with three events. There were no clinically relevant effects of treatments on vital signs, electrocardiogram or clinical laboratory variables. Concomitant administration of diltiazem doubled the exposure to ACT-178882 without affecting t½. The clinical significance of this increase is at present unknown and will need to be investigated in future clinical studies. Treatment with ACT-178882 alone or in combination with diltiazem was safe and well tolerated.