ACT 178882

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 (t?) 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 t?. 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.

Clinical pharmacology of single- and multiple-ascending doses of ACT-178882, a new direct renin inhibitor, and its pharmacokinetic interaction with food and midazolam

This study investigated the tolerability, safety, pharmacokinetics, and pharmacodynamics of ACT-178882, a new direct renin inhibitor, as well as its interaction with food and midazolam. Healthy male subjects received either single (10-1000 mg) or multiple doses (30-600 mg) administered once daily for 14 days of ACT-178882, placebo, or 20 mg enalapril in the fasted state. Following a 2-week washout, the single dose of 30 mg ACT-178882 was also administered in the fed state. In the multiple-ascending-dose part, subjects were dosed with midazolam on days -2, 2, and 12 to investigate interactions with CYP3A4. Dizziness and headache were the most frequently reported adverse events. No clinically relevant changes occurred for body weight, vital signs, clinical laboratory variables, and ECG although both enalapril and ACT-178882 tended to decrease systolic blood pressure. Following single doses of ACT-178882, t1/2 and tmax varied from 18.7 to 24.7 h and from 3 to 5 h, respectively, and food had no significant effect. Steady-state conditions were achieved after 4-6 days of dosing and accumulation was minimal. ACT-178882 pharmacokinetics were dose proportional. ACT-178882 but not enalapril dose-dependently increased Cmax and area under the concentration-time curve of midazolam. Single and multiple doses of ACT-178882 dose-dependently increased active renin and decreased plasma renin activity, whereas enalapril increased both variables. No effects on urinary excretion of creatinine, potassium, and the 6β-hydroxycortisol/cortisol ratio were observed, whereas sodium and aldosterone excretion was decreased by both ACT-178882 and enalapril. The current results with ACT-178882 warrant further clinical investigation of this renin inhibitor in hypertensive patients.

Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882

Purpose: ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties.
Methods: Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study.
Results: Exposure (as based on area under the curve) to simvastatin and 6β-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6β-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41.
Conclusions: This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.

Age and sex effects on the single- and multiple-dose safety and pharmacokinetics of the new renin inhibitor ACT-178882

Aim: To investigate the effect of age and sex on the single- and multiple-dose safety and pharmacokinetics of ACT-178882, a new direct renin inhibitor.
Methods: In the single-dose, open-label part of the study, healthy young and elderly male and female subjects received a dose of 300 mg ACT-178882. In the multiple-dose, double-blind, placebo-controlled part of the study, healthy elderly male and female subjects received ACT-178882 (300 or 600 mg) or placebo once-a-day for 14 days.
Results: Mild headache and diarrhea were the most common adverse events in the single- and multiple-dose parts, respectively. The frequency of diarrhea increased dose dependently, and no placebo subjects reported this adverse event. Administration of ACT-178882 did not result in any clinically relevant changes in ECG, vial signs, clinical laboratory, body weight, or physical examination. In the single-dose part and independent of sex, values for Cmax and AUC0-∞ were about 85% higher in elderly compared with young subjects, and t1/2 was about 5 h longer (29.3 vs. 24.1 h). In both age groups, plasma ACT-178882 concentrations were slightly higher in female versus male subjects. Following multiple-dose administration to elderly subjects, accumulation of ACT-178882 was moderate, about 1.8-fold, t1/2 was unchanged as compared with single-dose administration, sex effects were minimal, and the increase in the exposure with increasing dose appeared less than dose proportional.
Conclusion: Overall, single- and multiple-dose administration of ACT-178882 was well tolerated. No dose adaptation based on sex is necessary, whereas a dose reduction based on age could be considered.

A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.