Pharmacokinetics of felodipine in patients with impaired renal

Transcription

1 Br. J. clin. Pharmac. (1989), 27, Pharmacokinetics of felodipine in patients with impaired renal function B. EDGAR1'2, C. G. REGARDH2, P. O. ATTMAN3, M. AURELL3, H. HERLITZ3 & G. JOHNSSON2 1Department of Clinical Pharmacology, University of Goteborg, Goteborg, 2Cardiovascular Research, AB Hassle, Molndal and 3Department of Nephrology, Sahlgrenska Hospital, Goteborg, Sweden 1 The pharmacokinetics of felodipine and its effects on blood pressure and heart rate were studied in eight male patients aged between 28 and 57 years with a glomerular filtration rate, GFR, between 8 and 68 ml min-1, following single i.v. and oral administration. 2 Clearance, Cmax, AUC, Vss and V, of felodipine were unaffected by the renal disease. The metabolite excretion ("4C-labelled) was slower than in healthy subjects. Initial renal clearance of these metabolites correlated with individual GFR values. The total amount of the dose excreted in the urine was also decreased. Keywords felodipine pharmacokinetics renal function Introduction In more severe cases of hypertension combined with impaired renal function, vasodilators are added as second- or third-line treatment aftqr diuretics and/or P-adrenoceptor blockers. Older vasodilators, such as hydralazine, however, may cause water retention, despite concomitant treatment with a diuretic. Calcium antagonists have recently begun to be used more widely in the treatment of hypertension (Buhler et al., 1984; Muller et al., 1986; Moser, 1987). Felodipine, a new 1,4 dihydropyridine derivative with calcium-channel blocking activity, has been found to be a very selective dilator of smooth muscle in small blood vessels (Ljung, 1985; Nordlander et al., 1986) and to also have a diuretic effect (Edgar et al., 1985a; Katzman et al., 1986). Consequently, this compound is effective in reducing high blood pressure in hypertensive patients. Felodipine has also been shown to be effective in patients with hypertension associated with impairment of renal function (Herlitz et al., 1987). The pharmacokinetics of felodipine have previously been described in young healthy subjects and in patients with primary hypertension (Edgar et al., 1985b, 1987a) following single dose administration. These studies have shown that felodipine is a high clearance drug extensively bound to plasma proteins. The terminal half-life is about 25 h in the middleaged individual. The primary step in the metabolism of felodipine appears to be oxidation to the corresponding pyridine analogue (H152/37), (Hoffman & Andersson, 1987). The primary metabolite is further metabolised by cleavage of the methyl and ethyl esters and by oxidation of the methyl groups to the corresponding acids and alcohols. (Hoffman & Andersson, 1987) Less than 0.5% of a given dose is excreted in unchanged form and as H152/37 in the human urine (Edgar et al., 1985b). However, the kidneys play an important role in the elimination of the secondary metabolites as about 70% of a 14C-labelled i.v. dose is ultimately excreted as metabolites in urine. Ten metabolites have been identified, none of which have vasodilating activity (Hoffman &-Andersson, 1987). The objectives of this study were to evaluate the pharmacokinetics of felodipine in patients with impaired renal function and hypertension and to study the acute haemodynamic effects of orally and intravenously administered felodipine. Correspondence: Dr B. Edgar, Clinical Pharmacology CV, AB Hassle, S Molndal, Sweden 67

2 68 B. Edgar et al. Methods The study was approved by the Ethics Committee of the Medical Faculty of the University of Goteborg, and the Isotope Committee of Sahlgrenska Hospital, Goteborg. After receiving verbal and written information, all patients gave written consent to participate in the study. Patients Eight men, aged between 28 and 57 years, with impaired renal function and hypertension were included in the study. All patients were treated with metoprolol combined with a diuretic, while two patients were also given hydralazine (Table 1). All other medication, except the diuretic, was discontinued 2 days before and on study days. A renal function test, with 51Cr-EDTA, was performed within 1 month before the study. The glomerular filtration rate (GFR), measured by this method, ranged between 8 and 68 ml min-' (Table 1), and plasma creatinine varied from 143 to 546,umol I-1. The pharmacokinetic data from this study were compared with those from a group of eight healthy subjects (Edgar et al., 1985b), where plasma creatinine varied between 92 and 125,umol 1-1. Study design On two study days, at least 14 days apart, felodipine was given either as an oral solution, 10 mg, or as an individual i.v. dose of to 1.5 mg. The i.v. dose was administered by constant infusion for 10 to 20 min. Patient 5 received the oral dose only. The oral solution was swallowed directly from a glass bottle, which was rinsed twice with a total of 100 ml of water. Both doses were given in the morning after an overnight fast. Standard meals were given at 3, 5 and 8 h after dosing. The total amount of radioactivity in each dose did not, in any case, exceed 20,uCi as [14C]-felodipine. Serial blood samples were drawn from an antecubital vein. Sampling times after both oral and i.v. administration were: Predose, 15, 30, and 45 min, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 48, and 72 h. Additional blood samples were drawn 0, 3, 6, 10 min after the end of the i.v. infusion. After separation of plasma, samples were kept frozen until analysed. Urine was collected quantitatively for 120 h during the following time intervals: blank, 0-3, 3-6, 6-9, 9-12, 12-24, 24-48, 48-72, and h. The urine samples were weighed and 25 ml aliquots were saved and kept frozen until analysis. Supine blood pressures and heart rate were measured after 5 min rest up to 24 h after both drug administrations in both of the experiments. A semi-automatic device, Tonoprint (Weber & Anlauf, 1982), was used to record blood pressure and heart rate. The concentrations of felodipine and the primary metabolite (the corresponding pyridine derivative of felodipine with the code name H152/37) were measured in plasma and urine by gas chromatography and electron capture detection after extraction with toluene (Ahnoff et al., 1987). The method measures concentrations down to 0.5 nmol l-1 with a coefficient of variation of 15%. Total radioactivity in plasma and urine was measured by liquid scintillation counting (Edgar et al., 1985b). Protein binding studies were not an integral part of the study, as protein binding was only measured in three patients. However, since this information was required for a full pharmacokinetic assessment, blood was drawn from a further 15 patients with severe, chronic renal Table 1 Patient characteristics Age Weight GFR SBP/DBP Dutration of Treatment Diagnosis Patient (years) (kg) (ml min-') (mm Hg) disease (years) (1) (2) /95 3 MF CGN /90 17 M,F,H PCKD /85 6 M,F,H CGN /90 2 M,F CIN /90 3 MF CGN /105 1 M,B PCKD /95 11 M,HZ,AM CGN / M,F,AM CGN (1) M = metoprolol, F = frusemide, H = hydralazine, B = bendroflumethiazide, HZ = hydrochlorothiazide, AM = amiloride (2) CGN = chronic glomerulonephritis, CIN - chronic interstitial nephritis PCKD = polycystic kidney disease.

3 Felodipine pharmacokinetics and renal function 69 failure and from 12 healthy subjects. The binding of felodipine to plasma protein was determined by equilibrium dialysis against isotonic phosphate buffer ph 7.4. The dialysis time was 16 h and the temperature was 370 C. Calculations The extended least squares method, ELSFIT, (Peck et al., 1984; Sheiner & Beal, 1985) was used for non-linear regression analysis of the plasma drug concentration-time curve described by the multiexponential equation: C = E Cj.e-Ai-t i = I (1) In this equation, n was equal either to 2 or 3 depending on the time course of the plasma drug concentration. The Cis were the intercepts following transformation to a bolus dose (Loo & Riegelmann, 1970) and the Xis were dispositionrate constants. Plasma clearance (CL) of felodipine was calculated as: CL = Dose i, (2) AUCi.v. where AUC.v. was equal to the area under the plasma drug concentration-time curve from zero to infinity. The area was calculated by numerical integration of equation 1 for patients 1, 3, and 7, in whom plasma drug concentrations were measurable for at least 24 h after dosing. In patients 2, 4, 6 and 8, AUCI.v was determined by the equation: C0. T C -t'x AUCi.v = + AUC(T-,) + 2Z (3) 2 1n2 where C0 was the plasma drug concentration at the end of the infusion, T was the infusion time, C the concentration of drug in the last measurable plasma sample, and tl. the terminal half-life after the oral dose. The use of this half-life was necessitated by the short period of measurable plasma drug concentration in these four patients. At the end of this period the terminal phase had not been reached and the use of measured plasma drug concentrations would substantially underestimate t,,, and AUC after the i.v. dose. Previous studies have shown that the t,, felodipine after oral and i.v. dosing is virtually the same (Edgar et al., 1987a, b). AUC(T-,) was determined by the log-linear trapezoidal rule; t was the time of the last measurable plasma sample. The AUC after the oral dose was calculated using the equation: AUCoral = AUC(O,t) + ln2 (4) The linear trapezoidal rule was used for the ascending portion of the curve and the log-linear trapezoidal rule was applied to declining plasma drug concentrations. Intrinsic clearance, CLint, was calculated from the oral Dose AUCoral. The terminal half-life after i.v. and oral doses was determined from: ln2 te/x = Az (5) where X, was the smallest disposition rate constant by computer-fitting. The systemic availability of the oral dose, F, was determined by the equation: AUCI.v. Doseo,ai (6) The volume of distribution at steady-state, V, and the volume of distribution at apparent distribution equilibrium V were calculated by the equations: F = AUCoral,Doseiv V Dosei..AUMCi.,,. Dosei.,. T s- (AUCi.)2 2-AUCi.,. (7) V= Dose.,v (8) XZ-AUC,, where AUMC (the area under the first moment curve) was derived from: AUMC= tctdt+.c+ CA (9) The half-life of the total pool of radioactive metabolites in plasma and urine, was determined by linear regression analysis after log transformation of the individual data after the i.v. dose in the h interval (plasma) and h interval (urine). The initial renal clearance (CLR) of the total pool of radioactive metabolites was calculated from the slope of the regression line between the amount excreted in the urine during each collection interval and the AUC of these metabolites during the corresponding time intervals. Statistics All results are presented as mean values or mean + s.d. Student's t-test for paired observations was used to obtain the level of significance for the haemodynamic data. Observed differences

4 70 B. Edgar et al. were accepted as statistically significant at a probability level of P < The values of the parameters obtained in this study were compared with those from a study in healthy subjects (Edgar et al., 1985b) using the Mann-Whitney test. Results The mean plasma concentration vs time curve of felodipine and its total pool of radioactive metabolites following the i.v. dose are shown in Figure 1. The concentrations have been normalized to a dose of 1 mg. The plasma time course of intravenously administered felodipine declined in three distinct phases in patients 1, 3 and 7 while the concentrations in the plasma fell below measurable concentrations before the the third phase in the remaining four patients. The terminal half-life of felodipine in patients 1, 3 and 7 was 10.5, 18 and 13 h, respectively. Table 2 shows the individual -, L Figure 1 Mean plasma concentrations of felodipine (0, ) and total plasma radioactivity (0, 0 normalized to a 1 mg dose) after a single i.v. infusion of felodipine to patients (0, 0, n = 7) and healthy subjects (U, 0, n = 8). Table 2 Pharmacokinetic characteristics of felodipine in patients with impaired renal function after oral (10 mg) and i.v. ( mg) dosage. The values for the healthy subjects were reported by Edgar et al. (1985b) C, t,, AUC F t½ i.v. dose V V CLLt Patient (nmol 1-) (h) (nmol ri h) (%) (h) (mg) (1 kge) (I kge) (ml min-f) (1 min-f) (a) Mean s.d Healthy subjects Mean s.d (a) Undeterminable since no i.v. dose was given to the patient.

5 values of V, V,, and clearance derived from the intravenous data. The mean plasma clearance was 758 ± 267 ml min-' and the mean clearance from the blood was calculated to be 1083 ml min-', assuming a ratio of 0.7 between the concentration drug in blood and plasma (Edgar et al., 1985c). Mean plasma concentrations of felodipine during the first 12 h after the administration of the oral dose are shown in Figure 2. The individual pharmacokinetic characteristics derived from these data are listed in Table 2. Maximum concentration was attained 0.5 to 2 h after dosing. The variation in Cmax was only about two-fold between the patients, with a mean value of 35 ± 12 nmol l-l. On average, 18.0 ± 6.0% of the dose reached the systemic circulation as unchanged felodipine. The terminal halflife measured from plasma samples beyond 9 h after dosing varied between 5 and 43 h, giving a mean value of 20.8 ± 10.6 h. The mean intrinsic clearance from the blood was 6.4 ± min-'. The extent of plasma binding in the 15 patients with renal failure was ± 0.05%. This was significantly lower than in healthy subjects (99.64 ± 0.08%). Metabolites The time course of the mean plasma concentration of the primary metabolite, H152/37, following the oral dose of felodipine is shown in Figure 2. The time to peak was essentially the same for this metabolite as for felodipine but its maximum Felodipine pharmacokinetics and renal function concentration was higher. The mean ratio between Cmax values of felodipine and H152/37 was 0.7 ± 0.5. The corresponding ratio between the AUC values was 0.6 ± 0.4. The plasma concentrations of the metabolite following the i.v. dose were consistently lower than those of felodipine during the observation period in all patients. The terminal half-life of H152/37 determined from the oral data was 21.9 ± 8.3 h (Table 3). The time course of the mean plasma concentration of the total amount of radioactive metabolites following the i.v. dose is shown in Figure 1. Concentrations were normalized to a dose of 1 mg. Radioactivity in plasma reached a maximum level 1.5 to 6 h after dosing. The average maximum concentration of radioactive metabolites was twenty times that of felodipine. The terminal half-life of the radioactive metabolites in the plasma varied between 38.4 and h. The mean value of 64.7 ± 23.3 h was approximately three times longer than the terminal half-life of felodipine. Excretion of metabolites in the urine 71 An average of 54% of the dose was recovered in urine over a five-day period. The corresponding value after 3 days was 49%. Using the integral of the equation describing the excretion rate profile to infinity, a total of 67% was found to be excreted via the kidneys. The renal excretion rate of the metabolites declined in at least two phases of which only the slow last phase could be 150.5I T Time (h) Figure 2 Mean plasma concentrations (± s.d.) of felodipine (o) and its primary metabolite (H 152/37 *) after oral administration of 10 mg felodipine to eight patients with renal failure.

6 72 B. Edgar et al. Table 3 Elimination half-lives and initial renal clearance of metabolites in plasma and urine. The values for healthy subjects were reported by Edgar et al. (1985b) Plasma Total Total Urine H 152/37 metabolite metabolite Initial 112 Z., t,12 CLR Patient (h) (h) (h) (ml min-) Mean s.d Healthy subjects Mean n.d s.d n.d. = not determined determined in each individual. The mean halflife in this phase was 32.1 ± 4.7 h (Table 3). The cumulative excretion of radioactive metabolites following the i.v. dose of [t4cc-felodipine is shown in Figure 3. Renal clearance of radioactive metabolites decreased markedly during the experiment. Initial values determined from the first two urine specimens varied between 5.2 and 15.8 ml min-', with a mean value of 9.6 ± 3.6 ml min-'.80r 60 j 1.. X 40)i.T.. I I.. I...I (Table 3). Renal clearance during this period was significantly correlated with each GFR (r = 0.79, P < 0.05). Blood pressure changes Supine systolic blood pressure (SBP) was lowered by 10 ± 8% following the oral dose and the diastolic blood pressure (DBP) by 19 ± 10% form the morning value of 141 ± 18/90 ± 10 mm Hg 1 h after dose. This decrease in blood pressure was accompanied by an increase in heart rate of 31 ± 12%. The increase in heart rate was significant up to 2 h after dosing, while blood pressure was lowered for more than 4 h. After 4 h blood pressure was 129 ± 14/81 ± 10 mm Hg. The maximum decrease in DBP was significantly correlated with the corresponding plasma concentrations of felodipine (r = 0.87, P < 0.01) after the oral dose. 20 _7 Vn L- -i- ' Z0. Trn Ah) Adverse effects Headache was reported in four of the eight... patients after both oral and i.v. felodipine. One 80 10@0 120 patient experienced a vasovagal reaction during the infusion which was terminated prematurely Figure 3 Cumulative excretion of total (mean ± s.d.) after 7 min. Atropine (0.3 and 0.2 mg) was given radioactivity in urine after i.v. [14C 1]-felodipine to as blood pressure and heart rate continued to patients (o) and healthy volunteers. decrease. Blood pressure decreased from 117/77

7 Felodipine pharmacokinetics and renal function 73 mm Hg before dosing to 85/52 mm Hg when the infusion was stopped. Heart rate had then increased from a basal value of 77 beats min-' to 93 beats min-' and then began to decrease. When the infusion was stopped, the heart rate was 88 beats min-'. Before the second dose of atropine, the patient's blood pressure was 74/46 mm Hg with a heart rate of 50 beats min-'. The patient's head was lowered and feet raised and he recovered without sequelae. When the oral dose was given to the same patient no untoward effects were observed. Discussion The absorption characteristics of felodipine in these patients with impaired renal function were essentially the same as previously observed after a single oral dose given to individuals of the same age and with normal kidney function. The dose normalized Cmax was 3.4 nmol 1-1 mg-' in this study and 3.7 nmol l-1 mg-' in hypertensive patients (Edgar et al., 1985a). In most subjects the maximum concentration was reached during the first hour, as was the case in healthy subjects (Edgar et al., 1987b) and in hypertensive patients (Edgar et al., 1985a). The mean bioavailability of 18.3%, was not significantly different from that in healthy subjects (16.2%) (Edgar et al., 1985c) and hypertensive patients (18.3%) (Edgar et al., 1987a). Felodipine is characterized as a high clearance drug, eliminated almost exclusively by metabolism. It is more than 99% bound to plasma protein in healthy subjects (Edgar et al., 1985c). This binding is of the non-restrictive type as the clearance of felodipine from the blood approaches hepatic blood flow (Edgar et al., 1985b). The values of clearance of felodipine in the renal failure patient were in the same range as in young healthy subjects and in hypertensive patients with normal renal function (Edgar et al., 1987a) as were the values volume of distribution (10.8 ± kg-' (Edgar et al., 1985a, b). The mean terminal half-life after the oral dose (20.8 h) was comparable to that observed in hypertensive patients (Edgar et al., 1987a), but was longer than that in young individuals (14.4 h) (Edgar et al., 1985b). This difference was probably be an effect of age rather than disease (Landahl et al., 1988). Like felodipine, the primary metabolite is excreted in extremely small amounts by the kidneys (Edgar et al., 1985b). Accordingly, impaired renal function also had a negligible effect on the plasma concentrations and the terminal half-life of this metabolite, which were approximately the same as those for felodipine. While impaired renal function had a negligible influence on the pharmacokinetics of felodipine and the primary metabolite, the rate of elimination of secondary metabolites was significantly slowed by kidney dysfunction. The 3-day urinary recovery fell from about 74% of the given radioactive dose in healthy subjects to approximately 50% in these patients. On average 67% of the given dose would eventually be excreted in urine compared to 77% in the healthy subjects. The initial clearance of the radioactive metabolites was linearly related to GFR. Deviation from linearity in the later part of the experiment was probably due to formation of some metabolites having lower renal excretion rates. The terminal half-life of the metabolites in urine was, on average, twice as long in the patients studied as in healthy subjects (Edgar et al., 1985b). As in these subjects, the excretion rate fell biexponentially suggesting that metabolites with different rates of elimination are formed. The haemodynamic effects received after the oral dose of felodipine, were similar in these patients with reduced kidney function to those in patients with normal kidney function (Edgar et al., 1987a; Hedner et al., 1986). The large increase in heart rate (31%), offset the fall in SBP compared with the fall in DBP. No correlation was found between pretreatment blood pressure and the subsequent decrease, as has been reported for hypertensive patients (Edgar et al., 1987a). There were, however, fewer patients in this study. A correlation between the plasma concentrations of felodipine and maximum decrease in DBP was observed even though all patients were on individual doses of diuretics which may have complicated the analysis. In conclusion, no effects on the pharmacokinetics of felodipine could be attributed to renal disease. However the renal excretion rate of pharmacologically inactive metabolites was lowered in patients with renal dysfunction. The results obtained in this single dose study do not indicate any need for altered recommendations for patients with mild to moderate renal dysfunction compared with those recommended for patients of the same age with normal kidney function.

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