title: Drug-drug interaction study of ACT-178882, a new renin inhibitor, and diltiazem in healthy subjects.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. jasper.dingemanse@actelion.com
authors: Jasper
authors: J
authors: Dingemanse
authors: Laurent
authors: L
authors: Nicolas
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D003430:Cross-Sectional Studies; D003521:Cyclopropanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004110:Diltiazem / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D055815:Young Adult; D000092502:Renin Inhibitors
chemical_list: D002121:Calcium Channel Blockers; D003521:Cyclopropanes; D004110:Diltiazem; D011725:Pyridines; D000092502:Renin Inhibitors; C571787:MK-1597
references: Pol Arch Med Wewn. 2010;120(1-2):31-5
references: 20150842
references: Drug Metab Dispos. 2003 Jul;31(7):815-32
references: 12814957
references: Curr Med Res Opin. 2008 Sep;24(9):2627-37
references: 18687166
references: Clin Pharmacol Ther. 2012 May;91(5):771-3
references: 22513312
references: J Clin Pharmacol. 2011 Feb;51(2):218-28
references: 20413453
references: Fundam Clin Pharmacol. 2013 Dec;27(6):698-710
references: 22849770
references: Expert Rev Cardiovasc Ther. 2011 Apr;9(4):421-7
references: 21417713
references: J Clin Pharmacol. 2011 Nov;51(11):1561-70
references: 21209240
references: J Clin Hypertens (Greenwich). 2011 Dec;13(12):889-97
references: 22142348
references: Br J Clin Pharmacol. 1994 Mar;37(3):221-5
references: 8198928
references: Curr Med Chem. 2010;17(6):571-84
references: 20015034
references: J Clin Pharmacol. 2005 Apr;45(4):422-33
references: 15778423
references: Drugs Today (Barc). 2011 Jun;47(6):403-17
references: 21695283
references: J Renin Angiotensin Aldosterone Syst. 2011 Jun;12(2):102-12
references: 21059822
references: Clin Pharmacol Ther. 2000 Mar;67(3):267-74
references: 10741630
references: Circulation. 2005 Mar 1;111(8):1012-8
references: 15723979
references: Bioorg Med Chem Lett. 2010 Nov 1;20(21):6291-6
references: 20843690
references: Can J Cardiol. 2010 May;26(5):249-58
references: 20485689
references: Am J Geriatr Pharmacother. 2011 Dec;9(6):364-77
references: 22078863
references: Drug Metab Rev. 2009;41(2):67-76
references: 19514965
references: Expert Opin Drug Saf. 2012 Jan;11(1):83-94
references: 22022824
references: J Nephrol. 2011 Sep-Oct;24(5):541-9
references: 21786226