Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment

Abstract

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat.

Methods Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL_CR, ≥60 ml min⁻¹ ) and impaired renal function (CL_CR 40–59, 20–39, <20 ml min⁻¹ ) after 14 once daily oral doses of 10 mg temocapril hydrochloride.

Results For temocapril, there were no statistically significant differences in median t_max or mean C_max, AUC_SS, t_½,Z, CL/F between the four groups. Renal clearance, CL_R, for temocapril showed a linear decreasing trend with decreasing CL_CR [ mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min⁻¹]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean C_max or median t_max were detected. With decreasing mean CL_CR, mean AUC_SS for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml⁻¹ h] and t_½,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL_R for temocaprilat showed a linear decreasing trend with decreasing CL_CR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min⁻¹].

Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.

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