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

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.