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2 Br J Clin Pharmaol 1996; 42: Pharmaokinetis and haemodynami effets of the angiotensin onverting enzyme inhibitor ilazapril in hypertensive patients with normal and impaired renal funtion AMBROS1, H. W. VAN HAMERSVELT, J. F. M. WETZELS M. HUYSMANS of Mediine 1Department of Pharmaokinetis, Rohe, Basle, Switzerland 1 The pharmaokineti and pharmaodynami properties of the angiotensin onverting enzyme (ACE) inhibitor ilazapril were studied in 30 hypertensive patients with various degrees of renal funtion. 2 After a single oral dose, apparent ilazaprilat learane was dependent on renal funtion being , , and l l l h 1 (means+ s.d.) in patients with reatinine learanes (CLr) of >100, , 21-40, and 8-20 ml min 1, respetively. 3 During 11 weeks of treatment with ilazapril, doses were adjusted to the CLr and varied from 0.5 to 5.0 mg one daily. At 24 h after drug administration a lear antihypertensive response was seen only in the low learane groups (CLr< 40m l min-1). In ontrast, and despite higher one daily dosages, the deline of mean arterial pressure was small and ilazaprilat onentrations after 24 h were lower in the high learane groups. 4 This study demonstrates that hroni one daily treatment with ilazapril is effetive in patients with impaired renal funtion at dosages adjusted to reatinine learane. No aumulation was seen. Sine ilazaprilat learane was high in the high reatinine learane groups, a lear antihypertensive response in these groups was only seen at 3 h after drug administration. Keywords ilazapril renal failure hypertension pharmaokinetis proteinuria insuffiieny both after a single dose as well as during hroni treatment. The antihypertensive and antipro- The ACE inhibitor ilazapril is hydrolysed predominantly in the liver and blood to its ative form ilazaprilat. This metabolite is exreted mainly by the kidneys [1]. In patients with normal renal funtion teinuri effets of various dosages of ilazapril as well as their relation to reatinine learane (CLor) and angiotensin onverting enzyme (ACE) inhibition were studied at different times after drug administration. most of the unbound ilazaprilat is rapidly exreted in the first 8 h after drug administration. However, probably due to the high affinity of ilazaprilat for angiotensin onverting enzyme the terminal half-life of Methods this drug is as long as 40 to 50 h [1, 2]. In patients with renal insuffiieny only limited pharmaokineti and pharmaodynami data on hroni ilazaprilat administration are available [3-5]. Therefore, we investigated the pharmaokineti properties of ilazaprilat in hypertensive patients with various degrees of renal Thirty hypertensive patients without other serious ardiovasular disorders and with various but stable levels of renal funtion were seleted. At least 3 weeks before the start of the study all antihypertensive agents and any other drug possibly interfering with blood Correspondene: Dr H. J. Kloke, Division of Nephrology, University Hospital, Geert Grooteplein Zuid 8, 6500 HB Nijmegen, The Netherlands Blakwell Siene Ltd 615

3 616 H. J. Kloke et al. pressure regulation or renal funtion were disontinued. Patients were divided in four groups: reatinine learane and ACE ativity were performed by radioenzymati methods [1]. During hroni treatment these were (CLr)> 100 ml min 1(group A), CLr ml min" 1 measured at all visits at 24 h after drug administration (group B), CLr ml min 1 (group C) and CL r and additionally at week 2 and 4 at 3 h after drug 8-20 ml min ~1(group D). After three baseline measure- administration. At eah visit serum potassium and reatinine were measured. Other routine blood evalu- ations remained stable throughout the study. At baseline plasma renin ativity (PRA) was determined by radio- immunoassay [6]. In 24 h urine samples, onentrations of reatinine, sodium, potassium, and protein were measured at baseline and during hroni treatment. ments of haemodynami and laboratory parameters on separate days performed at the same time in the morning, patients reeived a single (either 0.5 or 1.0 mg) oral dose of ilazapril. During the subsequent 4 days, haemodynami and laboratory parameters were assessed at regular intervals. Thereafter, patients were treated during 11 weeks with a single daily dose of ilazapril (see below). Patients were ad vised to adhere to a onstant intake of Control visits were performed at weekly intervals during the first 4 weeks and further at week 7 and 11. sodium (150 mmol day 1) and potassium (60-70 mmol day 1) whih was onfirmed by urinary exretion. The study protool was approved by the Ethial Committee of the University Hospital in Nijmegen. All patients gave their written informed onsent. For analysis, only relative hanges of mean arterial Blood pressure measurements pressure (MAP) ompared with baseline were used. In one patient of group D the study was disontinued at At baseline standard sphygmomanometer supine diastoli blood pressure (BP) was greater than 90mmHg. All other BP and heart rate (HR) measurements were done by automati devies (DINAMAP, Crition In., Tampa, Florida or BOSCH EBM502, Bosh GMBH, Berlin, Germany). After 5 min supine rest, BP was measured at 1 min intervals for 3 min in supine position using the same arm throughout the study. During week 3 beause of peritonitis. In this patient only results of the single dose part were used for analysis. For determination of ilazaprilat pharmaokinetis individual data were analyzed by non-ompartmental methods [7]. Cilazaprilat peak onentrations (Cmax) and time to peak (imax) were diretly observed from analytial results. Sine the deline of the logarithm of ilazaprilat onentrations is essentially non-linear and may vary hroni treatment, BP and HR were always measured widely [2, 8], alulation of the area under the urve ' / «/ U J l 1 24 h after drug administration at the same time in the morning, with additional measurements 3 h after drug administration at weeks 2 and 4. The dose of ilazapril was inreased after 2 weeks of treatment (see below) if diastoli blood pressure redution 24 h after drug administration was less than 10% or if diastoli blood pressure remained higher than 90 mml-ig. Thus the ilazapril dose was inreased in seven, five, four and four patients of group A, B, C, and D, ref Sine patient numbers were small, data were analyzed to infinity may be unreliable. Therefore, the after the first dose was also alulated by the trapezoidal method to 24 h (AUC(0, 24 h)). Sine dosages of ilazapril were different in the high (AB) and low learane groups (CD), AUC (0, 24 h) and C were normalized to a dose of 1 mg for omparison of the results in the respetive learane groups. Apparent oral learane (CL0) was alulated as dose/auc(0, 24 h). Analysis of the pharmaokineti data from the single max for the ombined high and low learane groups AB and CD, respetively. dose part of the Pharmaokineti 11 by ANOVA. haemodynami data from multiple dose part (Table 3) were analyzed by distribution-free repeated measures analysis [9]. All other Drug dosage omparisons were assessed by Wiloxon s rank sum test and Wiloxon s signed Correlations were assessed by determining the orrelation oeffiient aording to Spearman or where appropriate aording to Pearson. A P value of 0.05 was onsidered as the level of statistial signifiane. Unless otherwise indi ated, values are given as means ± s.d. In the single dose part of the study patients of groups A and B reeived 1.0 mg ilazapril orally, whereas those of groups C and D reeived 0.5 mg. Chroni ilazapril doses were 2.5, 2.5, 1.0 and 0.5 mg one daily in groups A, B, C and D, respetively. If neessary, the dose was inreased one at week 2 to 5.0 mg (groups A, B), 2.5 mg (group C) or 1.0 mg one daily (group D). Patient ompliane was assessed by apsule ounting and measurements of plasma ACE ativity and ilazapri- Results lat onentrations. Single dose Other assessments Patient harateristis are given in Table 1. Pharmaokineti data are given in Figure 1 and Table 2. In During the single dose part of the study regular measurements of plasma onentrations of ilazaprilat ontrast to groups A and B, ilazaprilat onentrations delined slower in groups C and D. Aordingly, AUCs 1996 Blakwell Siene Ltd British Journal of Clinial Pharmaology 42,

4 Cilazapril pharmaokinetis, renal failure 617 Table 1 Patient harateristis at baseline Group inhibition and ilazaprilat onentrations was (P< 0.001) at 3 h after drug administration. A B D Chroni treatment Patients Age (years) 47 ± ± Cilazaprilat plasma onentrations, ACE inhibition, PRA Male/female 6/1 4/6 3/2 3/5 levels Throughout the study ilazaprilat onentrations Body weight (kg) ± at 24 h were onsiderably lower in patients from BP groups A and B ompared with patients from groups G systoli (mm Hg) 157 ± ±3 158±16 and D (Table 3). Inreasing the dose resulted in slightly diastoli (mm Hg) 98± higher ilazaprilat onentrations only in groups CD. CLr (ml min-1) ± After week 4 ilazaprilat onentrations measured at Patients with a h remained stable. Together with the lower ilazapri proteinuria of more lat onentrations ACE inhibition at 24 h was essentially than 1g day' i lower in patients of the high learane groups. ACE BP: blood pressure measured by sphygmomanometer; CLor: reatinine learane; means + s.d. are given. inhibition at 3 h after drug administration at week 2 and 4 was almost omplete in all patients. In patients treated with the same ( S ) and those treated with an inreased ( 1 ) dose, omparable levels of ACE inhibition 13 were seen at week 11 at 24 h: and 57+12% in E 03 o CD C CD Ü C o to the groups AB-S and AB-I (NS), and and 90+4% in the groups CD-S and CD-I (NS), respetively. PRA plasma onentrations at baseline were and nmol 1' i u _1 in group AB and CD (NS), respetively. In patients treated with the same ( S ) or an inreased ( 1 ) dose PRA onentrations were not signifiantly different. Blood pressure and heart rate Changes of mean arterial blood pressure are given in Table 3. In patients getting the same dose, blood pressure redution at 24 h «* * * * Q. T N O 5 remained essentially the same throughout the study. Inreasing the dose at week 2 had no additional effet Ü5 O CO E w is CL 3 1 -C<- '" '" S / / Time post dose (h) on blood pressure redution at 24 h in the high learane group (AB-I). In ontrast, a slight deline of blood pressure after dose inrease was observed in the patients of the low learane group (CD-I). Heart rate did not essentially hange in any group. No signifiant orrelation was found between BP derease on the one hand and baseline MAP, ilazaprilat onentrations, ACE inhibition or urinary sodium exretion on the other. Plasma ilazaprilat onentrations after a single Other assessments, adverse events In the low learane dose of 1.0 and 0.5 mg ilazapril (CLr>40 and <40 ml min"1, respetively). Cilazaprilat plasma onentrations of patients with an CLr of less than 40 ml min-1 are normalized to a dose of 1 mg. Means + s.e. mean are given CL ml min 1, n = 8;...CL ml r mm n 5: CL ml min-1 n = 10; r CLr > 100 ml min 7. groups CD serum reatinine and potassium onentrations had risen slightly from at baseline to j.mol 1 (P <0.05) at week 11 and from to mmol I-1 (P<0.05), respetively. Body weight essentially did not hange. Proteinuria dereased from at baseline to gram day 1 at week 11 (P<0.01) in the 10 patients with a proteinuria of more than 1 g day-1. No additional were larger in the low reatinine learane groups. Average time to peak onentration (fmax) was longer in patients with renal insuffiieny. Correlations were found between CLr and CL0 (r= , P<0.001), between redution in proteinuria was seen after inreasing the dose at week 2. Compliane assessed by the perentage of apsules used as expeted for the number of treatment days was 98 (93-101), 100 (94-102), 100 (99-105) and CLr and AUC(0, 24h) (r= , 1 PO.OOl) and 99 (97-101)% in group \ / ^ ± A, ' B, ' C, ' and D, ~ respetively * between CLr and t , P < 0.001). (medians and ranges; perentages of more than 100% (r. Compared with groups A and B, dereases of ACE inhibition were seen later in groups C and D (Figure 2). The orrelation oeffiient r between the degrees of ACE were possible sine the provided drug bottles had seven apsules in exess of the expeted number of treatment days). Two patients had short lasting dizziness during 1996 Blakwell Siene Ltd British Journal of Clinial Pharmaology 42,

5 618 H. J. Kloke et al. Table 2 Pharmaokineti parameters of ilazaprilat after a single oral dose Group A B D ANOVA Patients CLr (ml min-1) 130 ± ± 6 15 ± 4 AUC(0, 24 h) (ng ml"mi) ±27 134± ±47 ** Cmax (ng m l- 1 ) 8.8 ± ± ± 3.4 NS ^xnax (h) 2.0 (1-4) 2.5 (1-4) 3.0 (2-8) 6.0 (4-8) ** CL0 (1 h -1) 16.0 ± ± ± ±2.1 ** Unless otherwise indiated results are given as means ±s.d.; ** P< Abbreviations: ANOVA: analysis of variane, AUC(0, 24 h): area under the urve, Cmax: peak onentration, tmax: time to peak onentration given as medians (ranges), CL0: apparent total body learane. AUC(0, 24 h) and Cmax are normalized to a dose of one mg. Table 3 Cilazaprilat plasma onentrations (ng ml - 1), baseline supine mean arterial blood pressures (MAP) and their perent hanges during hroni treatment at 3 and 24 h after ilazapril intake in patients getting the same dose at week 2 ( S ) and in patients in whih dosage was inreased at week 2 ( 1 ) Group a AB-S AB-I CD-S CD-I Patients CLr (ml min - 1) 65 ±13 * ±11 23 ±8 Cilazapril dose (mg) Cilazaprilat onentrations Week 2 (3 h) 50.6 ± ± ±7.3 *58.9±38.1 (24 h) 2.0 ± ± ± ±2.2 Week 4 (3 h) 59.8 ± ± ±7.0 *60.8 ±25.8 (24 h) 2.3 ± ± ± ±3.7 Week 11 (24 h) 2.4 ± ± ± ±3.4 Me an arterial pressure Baseline (mm Hg) 111 ± ± ±7 118 ± 13 Week 2 (3 h) 17± 8 * 8 ± 6 7±7 8± 9 (24 h) i* 3 ± 4 11 ± i Week 4 (3 h) 17 ± 6 * 7±6 13 ±5 ± (24 h) 11 ±9 * 1±8 9± Week 11 (24 h) OC 1+OC * _ ± * P < 0.05 for ÀB-S vs AB-I and CD-S vs CD-I; results are given as means ±s.d the single dose part. In two patients dry ough was probably related to the treatment with ilazapril. to higher plasma onentrations of relatively less binding to ACE and elimination. Longer times to peak after lower dosages of ilazapril have also been reported in normal volunteers [2], In addition, the slower exretion of ilazaprilat Disussion in the low learane groups may have ontributed to the longer times to peak. Theoretially, slower intestinal In our patients with normal as well as in those with impaired renal funtion the pharmaokineti data of the absorption of ilazapril in the low learane groups may also explain this differene, but studies with other ACE single dose part were omparable with the results obtained by others [1, 3, 4]. A strong relationship inhibitors are not in favour of suh We an not ompare our results hanism [10]. the study of between reatinine learane on the one hand and AUC Pillastre et al who found a higher Cmax in patients with ind learane of ilazaprilat on the other hand was [3] observed. Time to peak was longer in patients with more severely impaired renal funtion. The lower dose patients with a low reatinine learane. Conentrations of ilazaprilat at 96 h were low and the deline of the given in the low learane groups was reason for logarithm of the onentration was not normalization to 1 mg. This may have biased the results regarding time to peak, sine the higher dose used in linear and showed a wide interindividual variation as reported by others [2, 8], The area from 96 h to infinity patients higher reatinine learanes may have was approximately half of the total area under the resulted in a larger amount of drug absorbed, leading urve. Thus, analysis of the total area under the urve 1996 Blakwell Siene Ltd British Journal of Clinial Pharmaology 42,

6 Cilazapril pharmaokinetis, renal failure response and may be related to the normal ourse of hroni renal failure in these patients. However, sine no ontrol groups were inluded, this remains diffiult 80 to assess. In onlusion, hroni treatment with ilazapril was safe in patients with an CLr of 8-20 ml min-1 and ml min-1 and a maximal one daily dosage of o 60 X ) JC 1.0 and 2.5 mg, respetively. No ilazaprilat aumulation was seen. Even at 24 h after drug administration ilazaprilat onentrations and degree of ACE inhibition ÜJ O < in these low learane groups were high and blood pressure response was adequate in most of the patients. In ontrast, in most patients with an CLr of more the 40 ml min ~1 no adequate blood pressure response was ahieved at one daily dosing. A ritial review of the pharmaokineti data was kindly performed by Dr F. Russel, Department of Pharmaology, University of Nijmegen, The Netherlands / / For their support and advie during the study we gratefully aknowledge W. P. L. van Boven M.D. (deeased), St Elisabeth Ziekenhuis, Tilburg; V. M. C. Verstappen M.D., St Maartens Time post dose (h) Gasthuis, Venlo; M. Kooien M.D., Bosh Medientrum, Figure 2 Degree of ACE inhibition after a single dose of 1.0 and 0.5 mg ilazapril (CLr>40 and <40 ml min-1, respetively). Means ±s.e. mean are given. 's-hertogenbosh, The Netherlands. Cilazapril was kindly supplied by F. Hoffmann-La Rohe AG, Basle, Switzerland. - C L, 5-20 ml min-1. n = 8 ;...CL r ml m m - i n = 5; CLor ml min-1. «= 10; CLr> 100 ml min n = l. Referenes from time zero to infinity was inaurate and therefore only results of AUC(0, 24 h) are presented here. During hroni treatment ilazaprilat onentrations measured at 24 h were onsiderably lower in the high learane than in the low learane groups, in aordane with previously reported data [4, 5, 11]. Only in patients with a low reatinine learane did the inrease in drug dosage ause an inrease in ilazaprilat onentrations at 24 h. However, no aumulation was seen in these groups. The duration of ACE inhibition was onsiderably longer in patients with more severe renal insuffiieny. The degree of ACE inhibition was losely related to ilazaprilat onentrations, thereby onfirming previous studies [4, 12]. As expeted from onentrations and degree of ACE inhibition a lear antihypertensive effet in all groups of patients was seen at 3 h after drug administration. In agreement with others [13-15], the blood pressure redution at 24 h remained small also after a dose inrease in 12 out of 17 patients of the high learane groups. In ontrast, blood pressure at 24 h was slightly lower after inreasing the dose in eight out of 12 patients with a low renal learane. However, the extent of blood pressure derease should be interpreted with aution sine a plaebo ontrol is laking. In patients with a proteinuria of more than 1 g day-1 ilazapril learly dereased urinary protein exretion by approximately 40%. Comparable antiproteinuri effets have been reported in the literature [5, 17]. Serum reatinine rose steadily only during the treatment in the low learane groups. This inrease was not influened by the ilazapril dose or degree of the antihypertensive 1 Williams PEO, Brown AN, Rajaguru S, et al. The pharmaokinetis and bioavailability of ilazapril in normal man. Br J Clin Pharmaol 1989; 27: 181S-188S. 2 Franis RJ, Brown AN, Kler L, et al. Pharmaokinetis of the onverting enzyme inhibitor ilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematial model. J Cardiovas Pharmaol 1987; 9: Fillastre JP, Moulin B, Godin M, et al Pharmaokinetis of ilazapril in patients with renal failure. Br J Clin Pharmaol 1989; 27: 275S-282S. 4 Shionori H, Gotoh E, Takagi N, Takeda K, Yabana M, Kaneko Y. Antihypertensive effets and pharmaokinetis of single and onseutive doses of ilazapril in hypertensive patients with normal and impaired renal funtion. J Cardiovas Pharmaol 1988; 11: Kloke HJ, Wetzels JFM, van Hamersvelt HW, Koene RAP, Kleinbloesem CH, Huysmans FTM. Effets of nitrendipine and ilazapril on renal hemodynamis and albuminuria in hypertensive patients with hroni renal failure. J Cardiovas Pharmaol 1990; 16: Sealey JE, Laragh JH. Searhing out low renin patients: limitations of some ommonly used methods. Am J Med 1973; 55: Gibaldi M. Compartmental and nonompartmental Pharmaokine-tis. In Biopharmaeutis and Clinial Pharmaokinetis. Philadelphia: Lea & Febiger, 1991: Meredith PA, Elliott HL, Reid JL, Franis RJ. The pharmaokinetis and angiotensin onverting enzyme inhibition dynamis of ilazapril in essential hypertension. Br J Clin Pharmaol 1989; 27: 263S-266S. 9 Koziol JA, Maxwell DA. A distribution-free test for tumorgrowth urve analyses with appliation to an animal tumor immunotherapy experiment. Biometris 1981; 37: Blakwell Siene Ltd British Journal of Clinial Pharmaology 42,

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