Single dose and steady state pharmacokinetics of temocapril and temocaprilat in young and elderly hypertensive patients

Abstract

Aims The aim of this study was to determine the potential impact of age on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat, in hypertensive patients. Methods Male and female patients with mild to moderate essential hypertension (DBP 95-114 mmHg inclusive) were allocated to two age groups: young, ∏40 years; elderly, Á69 years, (n=18 per group). In Part I of the study, subjects took a single oral tablet dose of 20 mg temocapril hydrochloride following an overnight fast. In Part II they took seven once daily oral tablet doses of 20 mg temocapril hydrochloride. Pharmacokinetic profiles were determined after the single and the last dose. Trough plasma samples were taken before each dose in Part II. Urine was collected for 24 h following the single and the last dose. Results Steady state was reached within 1 week in both groups. Statistically significant differences were detected in AUC and AUC ss for temocaprilat as well as in CL R for temocapril and temocaprilat, respectively, after a single dose and at steady state. All other pharmacokinetic parameters for temocapril and temocaprilat did not show any significant difference. Conclusions The pharmacokinetic differences detected in the elderly do not require a dose adjustment per se. Nonetheless, a lower starting dose may be appropriate as elderly hypertensive patients are usually considered to be at an increased risk of first dose hypotension at the onset of treatment with an ACE inhibitor. In this study, we investigated the pharmacokinetics of temocapril and temocaprilat after a single oral tablet dose have been shown to prolong life in patients with congestive heart failure [2] and post myocardial infarction [3]. Moreover, and after seven once daily doses of 20 mg temocapril hydrochloride in one target population for ACE inhibitors, several studies indicate beneficial effects of this class of drugs for preserving renal function in patients with diabetic [4][5][6] namely young (≤40 years) and elderly (usually ≥65 years) hypertensive patients. The study design, a single dose and nondiabetic nephropathy [7].With the exception of captopril [8] and lisinopril [9], administration followed by multiple doses supposed to result in steady state conditions, is the most suitable way to get ACE inhibitors are administered as prodrugs which require bioactivation by nonspecific esterases [10]. Thus, pharmacothe full range of information on the disposition of a prodrugtype ACE inhibitor. The dose studied, 20 mg, was selected kinetic evaluation of prodrug-type ACE inhibitors has to focus on the disposition of both the parent compound as as it is an effective dose with respect to blood pressure lowering [11]. As the population of hypertensive patients the source of the pharmacologically active metabolite and the active metabolite itself.consists of more and more elderly and very elderly (usually ≥75 years), a particular emphasis was laid on the potentialinfluence of age on the pharmacokinetics of this drug. 2-(2-thienyl)-1,4-thiaz...