Br J Clin Pharmacol 1997; 44: 531–536 Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment K. Pu¨chler,1 K. M. Eckl,2 L. Fritsche,3 K. Renneisen,1 H.-H. Neumayer,3 B. Sierakowski,1 A. T. J. Lavrijssen,4 T. Thomsen2 & I. Roots5 1Sankyo Europe GmbH, Duesseldorf, Germany, 2PharmPlanNET Contract Research GmbH, Moenchengladbach, Germany, 3Medizinische Klinik und Poliklinik V (Nephrology), Charite´, Humboldt University, Berlin, Germany, 4Oosterschelde Hospital Goes, The Netherlands, 5Institute of Clinical Pharmacology, University Clinic Charite´, Humboldt University, Berlin, Germany 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 −1 (creatinine clearance determined via 24 h urine sampling, CLCR, ≥60 ml min ) −1 and impaired renal function (CLCR 40–59, 20–39, <20 ml min ) after 14 once daily oral doses of 10 mg temocapril hydrochloride. Results For temocapril, there were no statistically significant diVerences in median tmax or mean Cmax, AUCSS, tD,Z, CL/F between the four groups. Renal clearance, CL , for temocapril showed a linear decreasing trend with decreasing CL [mean R − CR (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 diVerences in mean Cmax or median tmax were detected. With decreasing mean CLCR, mean AUCSS for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): −1 2115 (565) to 4989 (2338) ng ml h] and tD,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CLR for temocaprilat showed a linear decreasing trend with −1 decreasing CLCR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min ]. Conclusions These results indicate that impaired renal function has only a limited eVect 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. Keywords: temocapril, temocaprilat, ACE inhibitor, renal failure, pharmacokinetics through the alternative route [3, 4]. Because of this, the Introduction drugs can be administered without dosage adjustment to Angiotensin converting enzyme (ACE) inhibitors are a subjects with mild to moderate renal impairment. group of drugs that have assumed an increasingly prominent Temocapril (INN) hydrochloride is (+)-[(2S,6R)-6-[[(S)- role in the management of hypertension; they are eVective 1-(ethoxycarbonyl)-3-phenylpropyl] amino]-5-oxo-2-(2- and well-tolerated and oVer certain advantages in some thienyl)-1,4-thiazepan-4-yl] acetic acid monohydrochloride, subgroups of patients such as diabetic hypertensives. A large a recently developed carboxyl-containing ACE inhibitor number of ACE inhibitors are now available, the great with a dual excretion pathway. It is the ester prodrug of the majority of which are eliminated predominantly through pharmacologically active diacid metabolite temocaprilat. the kidneys [1, 2]. As a result, elimination is aVected by Dose linearity was demonstrated for temocaprilat over the renal impairment in a predictable manner and reductions of dose range of 5–40 mg once daily [Sankyo, data on file]. In doses of ACE inhibitors are generally recommended in this study, we investigated the pharmacokinetics of temocap- patients with reduced renal function [1, 2]. However, some ril and temocaprilat after 14 once daily oral doses of 10 mg of the more recent ACE inhibitors, such as fosinopril and temocapril hydrochloride in hypertensive Caucasian patients spirapril, have dual elimination pathways, both renal and with normal and impaired renal function. The dose studied, hepatic, and when one route of elimination is impaired 10 mg, was selected as it is an eVective dose with respect to there is a compensatory increase in the fractional excretion blood pressure reduction but it is at the lower end of the therapeutic range in Caucasians [Sankyo, data on file]. It Correspondence: Dr Bernd Sierakowski, Sankyo Europe GmbH, Immermannstrasse was expected to be safe and to produce reliable and 45, D-40210 Duesseldorf, Germany. measurable plasma concentrations. © 1997 Blackwell Science Ltd 531 K. Pu¨chler et al. Methods Sample collection and assays On days 5, 8, 11, 12, 13 and 14 predose, blood samples were Patient selection and treatment taken for trough measurements. After the last dose on day Four centres participated, three of which were in Germany 14,bloodsamplesweretakenat0.5,1,1.5,2,3,4,6,8,12, (patients recruited: n=30) and the fourth in the 16, 24, 36, 48, 72, 96 and 120 h. Total urine output was Netherlands (n=2). All subjects provided written informed collected from 0 to 120 h. Blood was drawn into heparinised consent and the study was conducted in accordance with tubes and subjected to centrifugation at 1600 g at 4° Cfor the German Medicines Act, the EU Note for Guidance on 10 min. Plasma and urine samples were stored at −20° C Good Clinical Practice, and the Declaration of Helsinki. until analysis. Plasma and urine concentrations of temocapril Ethics committee approval was obtained before study and temocaprilat were determined using capillary gas chroma- commencement. tography-negative ion chemical ionization mass spectrometry Adult Caucasian subjects with mild to moderate essential (GC-MS) [5]. A deuterated analogue was used as internal hypertension (diastolic blood pressure between 95 and standard and all three compounds were extracted from plasma 114 mmHg, systolic blood pressure 220 mmHg or lower) and urine using a two-stage solid phase procedure with Sep- who had been treated with an ACE inhibitor other than Pak C18 and Sep-Pak silica cartridges. Sequential derivatization fosinopril for at least 3 months were eligible. The degree of carboxylic acid and secondary amino groups was carried of renal impairment was based upon creatinine clearance out using diazomethane and trifluoroacetic acid anhydride, (CLCR) which was assessed by 24 h urine collection on 2 respectively. Negative ion chemical ionization of the deriva- consecutive days during a 3-week screening interval. The tives using methane as reagent gas produced intense high result of the first measurement was set at 100%. The mass fragments ideal for selected ion monitoring. The second had to be in the range 80–120%. If not, a third combination of capillary gas chromatography, derivatization assessment had to be performed which, setting the and monitoring of specific high mass negative ions ensured second at 100%, had to be within the range of 80–120%. no interference from coextracted endogenous plasma compo- The mean of the two relevant results was taken. The nents. Imprecision of the assay did not exceed 3.3% and subjects were grouped according to their CLCR values 11.8% following analysis of CS-622 (temocapril) and as follows: RNH-5139 (temocaprilat) in plasma (8.8% and 3.6%, ≥ −1 Group A CLCR 60 ml min respectively, in urine). Inaccuracy for both analytes did not −1 − + − + Group B CLCR 40–59 ml min exceed 9.8% to 3.9% in plasma ( 9.5% to 12.1% in −1 Group C CLCR 20–39 ml min urine). The lower limit of quantification (LLQ) was < −1 −1 Group D CLCR 20 ml min 0.50 ng ml for both analytes in plasma and urine. Subjects with clinically relevant heart failure, coronary artery disease, valvular defects ( particularly those impeding cardiac Pharmacokinetic evaluation and statistical analysis outflow), renal artery stenosis, only one intact kidney, chronic haemodialysis or any renal condition that might Pharmacokinetic data were analysed by noncompartmental have aVected safety were excluded from the study. Subjects techniques using the TopFit 2.1 software. For peak concen- with clinically significant intercurrent medical conditions tration in plasma, Cmax, and time to reach peak concentration, which might have interfered with the evaluation of tmax, observed values were taken. The apparent terminal pharmacokinetics were also ineligible. elimination rate constant, lZ, was determined by linear All subjects had their ACE inhibitors withdrawn 1 day regression of the terminal phase of the log plasma concen- prior to the start of dosing. Subjects with normal renal tration vs time curve. The terminal half-life, tD,Z,was function were allowed to take between one and three calculated as (ln 2)/lZ. Area under the plasma concentration additional antihypertensive drugs including diuretics (e.g. vs time curve was calculated by the linear-logarithmic frusemide, calcium-antagonists, and vasodilative drugs such trapezoidal rule up to 24 and 120 h for AUCSS and as clonidine or dihydrallazine), oral contraceptives, paraceta- AUC(0,120 h), respectively, and, for AUC, up to the last mol or aspirin and, if necessary, the previously used ACE time at which the concentration was equal to or above the inhibitor after the 48 h postadministration sample. Those LLQ, AUC(0,t), and extrapolated to infinity by dividing the with impaired renal function were allowed to take drugs as plasma concentration at time t by lZ and adding this value to above plus insulin, calcium carbonate, cholecalciferol, and AUC(0,t). The apparent total plasma clearance, CL/F,was vitamin preparations. calculated by dividing the dose (10 mg) by the AUCSS for Subjects took temocapril hydrochloride (film-coated temocapril. The renal clearance from plasma, CLR,was tablets supplied by Sankyo Pharma GmbH, Munich, calculated by dividing urinary recovery of temocapril, Ae, Germany) orally at a dose of 10 mg once daily for 14 days. and temocaprilat, Ae(m), by the related AUC(0,120 h). Medication was taken with 200 ml water after a continental The temocapril and temocaprilat trough plasma concen- breakfast between 07.00 h and 09.00 h for the first 13 days trations of days 5, 8, 11, 12 and 13 were analysed by and, after fasting overnight for at least 10 h, on day 14 (last regression analysis.