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document
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 .
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Intervention_Pharmacological
diltiazem
58209
Intervention_Pharmacological
ACT-178882
58210
Intervention_Pharmacological
diltiazem
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Outcome_Other
effect
58212
Participant_Condition
healthy
58213
Participant_Condition
healthy
58214
Participant_Condition
healthy
58215
Participant_Age
young
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Participant_Sex
male