Clinical Pharmacokinetics of Lercanidipine

Abstract

Lercanidipine hydrochloride (HCl) (Zanidip) is a new calcium-channel blocker structurally related to the 1,4-dihydropyridines (Fig. 1). In common with other calcium antagonists of the same group, such as felodipine, isradipine, nicardipine, and amlodipine, lercanidipine has a chiral center, accounting for the presence of two enantiomers, with S(+)-lercanidipine being the more active (eutomer) for antihypertensive activity.FIG. 1.: Structural formula of lercanidipine HCl. Chemical name: (±)3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-2-[(3,3-diphenylpropyl) methylamino]-1, 1-dimethylethyl methyl ester hydrochloride. Physicochemical characteristics: Atomic structure, C36 H41 N3 O6 · HCl; Molecular weight, 648.205; Melting point (°C), 185-190; Solubility in water, 10 mg/100 ml. Partition coefficient (octan-1-ol/water): logP = 6; Dissociation constant (37°C), pK'a = 6.83.Because lercanidipine HCl is administered as the racemic form, to investigate the pharmacokinetics of its enantiomers a stereospecific HPLC/UV analytical method has been developed in our laboratories (1). The limit of quantitation obtained with adequate accuracy and precision was 0.5 ng/ml. Twelve pharmacokinetic studies have been undertaken, involving 63 healthy volunteers and 74 patients, and all were performed in accordance with GCP guidelines. Three studies were performed using encapsulated drug in solution, and the others were carried out using a tablet formulation, later used for pivotal clinical studies. A 14C-radiolabeled preparation was used in one study (2). ADME AFTER ORAL ADMINISTRATION OF [14C]LERCANIDIPINE HCl Single oral doses of 20 mg 14C-labeled lercanidipine HCl, as a solution in polyethyleneglycol 400 contained in a gelatin capsule, were administered to four healthy male subjects, median age 39 years (2). Samples of blood and all urine and feces were collected for 7 days after dosing. Absorption The absorption from the gastrointestinal tract was rapid, with Tmax ranging from 0.75 to 1.5 (mean 1.2 ± 0.4 SD) h. The dose absorbed corresponded to at least 44% of the administered dose. The pharmacokinetic parameters of the radioactivity and unchanged drug are summarized in Table 1.TABLE 1: Mean (±SD) pharmacokinetic parameters of radioactivity and unchanged drug in four healthy male subjects after a single 20-mg oral dose of [14C]lercanidipine HCl dissolved in polyethyleneglycol 400Between 8 and 12 h there was a small secondary peak in the level of radioactivity, suggesting a small amount of enterohepatic recirculation of the metabolites (Fig. 2). The plasma concentration-time profile showed that the concentration of radioactivity significantly and consistently exceeded that of unchanged drug up to 36 h, thus demonstrating the presence of circulating metabolites. The percent proportion of the plasma radioactivity represented by the unchanged drug during the first 8 h of the quantifiable period was 2.3% at 1 h and declined progressively to 0.7% at 8 h.FIG. 2.: Mean concentrations of radioactivity and unchanged lercanidipine in plasma over 36 h after oral administration of [14C]lercanidipine HCl (20 mg) to four male subjects.Distribution Binding of [14C]lercanidipine to the human plasma proteins in vitro could not be determined reliably by ultrafiltration or equilibrium dialysis because of its appreciable binding to the membrane used in each case. However, the uncorrected ultrafiltration results obtained indicated that at a concentration similar to 5 and 20 Cmax binding was >98 and >99%, respectively, similar to that observed in rats and dogs, the species used in the the long-term toxicity studies. Radioactivity concentrations in ultrafiltrates of post-dose plasma samples taken from the treated subjects indicated that 76-83% of the radioactivity taken at or close to Tmax was protein-bound. Although of limited value, these data suggest that lercanidipine was extensively bound to human plasma proteins. Whole-blood: plasma radioactivity concentration ratios were generally in the range of 0.5-0.6. indicating that uptake of drug-related material into erythrocytes was not extensive. The apparent volume of distribution for lercanidipine, calculated from data obtained after 2 mg intravenous infusion (15 min) in healthy male volunteers (3), was in the range of 2-2.5 L/kg. Metabolism When orally administered, lercanidipine HCl undergoes extensive biotransformation, and practically no unchanged drug is present in urine and feces. The metabolism of lercanidipine involves aromatization of the heterocyclic ring, oxidative loss of the N side-chain, and its glucuronidation. Other pathways involved include nitro reduction, N,N-didealkylation, and glucuronidation (Fig. 3).FIG. 3.: Proposed biotransformation pathways of [14C]lercanidipine in healthy male subjects after oral administration of [14C]lercanidipine HCl.Aromatization of the heterocyclic ring and hydroxylation of the side-chain, with consequential loss of N - methyl -N- (3,3 - diphenyl) propylamine groups, produce a primary alcohol, metabolite M8, which undergoes subsequent glucuronidation to metabolite M4. Nitro reduction with N,N-didealky-lation leads to the formation of an amine metabolite M5. Another metabolite, M7, was structurally closely related to M8 but could not be characterized because it was present in very small amounts. M7 was conjugated with glucuronic acid to produce M5. Another metabolite, M2, could not be characterized; after enzymatic hydrolysis it gave a peak at the same retention time as M4. The TLC radiochromatograms of urine are shown in Fig. 4.FIG. 4.: Thin-layer radiochromatograms of 0-2-h human urine after oral administration of [14C]lercanidipine HCl (20 mg). (a): Untreated; (b): β-glucuronidase/sulfatase-treated.Two metabolites, M4 and M8, dominated the plasma samples taken shortly after administration of the drug, whereas metabolites M2 and M5 were also present but in low concentrations only (Fig. 5). Because the two metabolites M4 and M8, which are the primary alcohols, contain a pyridine rather than a dihydropyridine ring, it is unlikely that they contribute to the pharmacologic activity of the drug. Quantitative data on the metabolites are listed in Tables 2 and 3. PA3 has been successively isolated by extraction of urine with ethyl acetate at pH 1.0 (Fig. 3).FIG. 5.: Thin-layer radiochromatograms of 2-h human plasma after oral administration of [14C]lercanidipine HCl (20 mg). (a): Untreated; (b): β-glucuronidase/sulfatase-treated.TABLE 2: Proportion of the principal radioactive components in human plasma separated by TLC after oral administration of[14C]lercanidipine (20 mg)aTABLE 3: Total amounts of principal radioactive components in excreta after oral administration of [14C]lercanidipine (20 mg) in male subjectsaExcretion The 93.4 to 96.1% (mean 94.2 ± 1.3% SD) of the administered radioactivity was recovered in the excreta during the subsequent 7 days. This was composed of about 43.8% in the urine and 50.4% in the feces (Fig. 6). No unchanged drug was detected in the urine, demonstrating an effectively complete biotransformation of lercanidipine before excretion.FIG. 6.: Mean cumulative excretion of radioactivity in urine and feces after oral administration of [14C]lercanidipine HCI (20 mg) to male subjects.PHARMACOKINETICS OF ENANTIOMERS In an open-label randomized, three-treatment, three-period crossover study, 12 healthy male volunteers, mean age 26 ± 3 years, weight 70 ± 4 kg, height 175 ± 5 cm, were administered single oral doses of 10 mg S(+)-lercanidipine, 10 mg R(−)-lercanidipine, or 20 mg (±)-lercanidipine as 2% w/w propyleneglycol solution in gelatin capsules (4). The profile of the two enantiomers was similar to that obtained when 20 mg of the racemate was administered. Administration of the racemate resulted in statistically significant higher Cmax and area under the curve (AUC) of each enantiomer compared to their administration as the single enantiomer. The Cmax and AUC of the S(+)-enantiomer were on average 1.2 times higher than those of the R(−)-enantiomer. The parameters obtained are listed in Table 4. There was no evidence of in vivo chiral inversion. The presence of the R-enantiomer spares the eutomer from first-pass metabolism and supports the decision to develop the racemic form of lercanidipine.TABLE 4: Mean values (±SD) of lercanidipine (lerc) enantiomer pharmacokinetic parameters in healthy male volunteers (n = 12) administered single oral doses of 10 mg S(+)-lercanidipine HCl, 10 mg R(−)-lercanidipine HCl, or 20 mg (±)-lercanidipine HCl capsulesDOSE-KINETICS LINEARITY To 12 healthy male volunteers, mean age 26 ± 5 years, weight 71 ± 10 kg, height 176 ± 4 cm, single oral doses of 10, 20, and 40 mg lercanidipine HCl tablets were administered (5). The data obtained are reported in Table 5.TABLE 5: Mean values (±SD) of S(+)-lercanidipine pharmacokinetic parameters in healthy male subjects (n = 12) after 10-, 20-, and 40-mg single oral doses of lercanidipine HCl tabletsDespite no significant increase in terminal half-life, the AUC increased disproportionately between 10 and 20 mg and quite markedly between the 20 mg and 40 mg. The disproportionate increase of Cmax was only modest compared to AUC in the dose range of 10-20 mg. These data suggest a saturable first-pass metabolism just above the 10-mg dose. No adverse events occurred, indicating a wide therapeutic margin for lercanidipine HCl. PHARMACOKINETIC PARAMETERS AFTER SINGLE AND REPEATED DOSES Twelve patients with mild to moderate hypertension, nine men and three women, mean age 49 ± 16 years, weight 71 ± 7 kg, and height 171 ± 8 cm, were administered 10 or 20 mg lercanidipine HCl tablets daily for 7 days on two separate occasions (6-month interval) (6,7). The data obtained are shown in Table 6. These data show that there is no significant accumulation after the 10-mg daily dose. After a 20-mg daily dose, slight but significant accumulation was observed. This is consistent with the findings of the dose-proportionality study described previously. The profiles of S(+)-lercanidipine plasma concentrations after single and repeated administration are shown in Figs. 7 and 8.TABLE 6: Mean values (±SD) of S(+)-lercanidipine pharmacokinetic parameters in mild to moderately hypertensive patients (n = 12) after 10 mg or 20 mg lercanidipine HCl tablet daily for 7 daysFIG. 7.: S(+)-lercanidipine mean plasma levels after single and repeated (q.d. for 7 days) oral administration of 10 mg lercanidipine HCI to mild to moderately hypertensive patients (n = 12).FIG. 8.: S(+)-lercanidipine mean plasma levels after single and repeated (q.d. for 7 days) oral administration of 20 mg lercanidipine HCI to mild to moderately hypertensive patients (n = 12).FORMULATION EFFECT To compare the relative bioavailability of tablets and soft gelatin capsules of lercanidipine HCl, 12 healthy male volunteers, mean age 28 ± 5 years weight 74 ± 8 kg, height 178 ± 6 cm, were administered 20 mg of the drug in a single oral dose (8). The parameters derived are shown in Table 7. The capsule was absorbed somewhat more rapidly, but the levels appeared to be more erratic than those after the tablet For the S(+)-enantiomer pharmacokinetic parameters, there was a significant difference between the two formulations, with the tablet Cmax being 83% of the capsule Cmax and AUC being 87% of the capsule AUC These differences are not considered clinically significant because they are small. There were large interindividual differences, and the therapeutic effect of lercanidipine did not appear to be correlated with its plasma concentration.TABLE 7: Mean values (±SD) of lercanidipine enantiomer pharmacokinetic parameters in male healthy volunteers (n = 9) after single 20-mg oral doses of lercanidipine HCl tablet or capsuleEFFECT OF FOOD A high-fat meal, the one proposed by FDA that has a high kcal/volume content, is likely to slow stomach emptying and can be referred to as the maximal interaction. It was shown (5) to increase (by approximately threefold) the availability of lercanidipine HCl taken within 5 min by 12 healthy male volunteers age 26 ± 5 years, weight 71 ± 10 kg, height 176 ± 4 cm (Table 8). The observed reduction of the first-pass effect might be explained by an increase in hepatic blood flow owing to the food and/or by absorption via the lymphatic route.TABLE 8: Mean values (±SD) of lercanidipine enantiomer pharmacokinetic parameters in healthy male volunteers (n = 12) after single 20-mg oral doses of lercanidipine HCl tablets under fasting conditions or immediately after a high-fat mealA further study (9) performed to investigate the influence of time of dosing on drug-food interaction confirmed that a high-fat meal increases oral bioavailability of lercanidipine. This increase was evident when the drug was given between 5 min and 2 h after the meal compared to administration in the fasting state. Some interaction was also observed after a carbohydrate-rich meal. No difference in heart rate was observed after the different treatments. Based on the results obtained thus far, it is advisable to take lercanidipine before meals. PHARMACOKINETICS IN SPECIAL POPULATIONS The pharmacokinetics of lercanidipine are only minimally altered in the elderly, in cirrhotics, and in patients with mild to moderate renal dysfunction. Consequently, no adjustment in the dosage is required in these patients, especially as the duration of the antihypertensive effect far exceeds its plasma half-life. In contrast, however, the pharmacokinetics of lercanidipine are substantially altered in severe renal dysfunction, and these patients require careful titration. These findings for lercanidipine are in agreement with similar findings for most other dihydropyridines. PHARMACOKINETICS IN PATIENTS WITH MILD TO MODERATE HYPERTENSION When the single-dose data for S(+)lercanidipine in young healthy volunteers (mean age 26 ± 5 years) are compared with those obtained in mild to moderately hypertensive patients (mean age 49 ± 16 years), greater bioavailability in patients, with AUC and Cmax higher and Tmax greater, is observed (6,7) (Table 9).TABLE 9: Mean values (±SD) of S(+)-lercanidipine pharmacokinetic parameters in young healthy volunteers (n = 12) and mild to moderately hypertensive patients (n = 12) after a single 10- or 20-mg oral dose of lercanidipine HClEFFECT OF AGE IN PATIENTS WITH HYPERTENSION Twelve elderly hypertensive patients, 5 men and seven women, age 68 ± 3 years, weight 65 ± 6 kg, height 165 ± 7 cm, received 20 mg lercanidipine HCl tablets daily for 7 days (10). The resulting S(+)-lercanidipine pharmacokinetics parameters are shown in Table 10, compared with the corresponding data (6) in non-elderly patients. The data suggest that there is no significant difference in the pharmacokinetics of lercanidipine between hypertensive patients younger than 65 and those above 65 years of age. Figure 9 shows the S(+)-lercanidipine plasma concentrations profiles in elderly and non-elderly patients.TABLE 10: Mean values (±SD) of S(+)-lercanidipine pharmacokinetic parameters in elderly (n = 12) and non-elderly (n = 12) mild to moderately hypertensive patients after a single 20-mg oral dose of lercanidipine HCl tabletFIG. 9.: S(+)-lercanidipine mean plasma levels (n = 12) after repeated oral administration of 20 mg lercanidipine HCI daily for 7 days.RENAL DISEASE IN PATIENTS WITH HYPERTENSION In a single-blind, two-period study. 14 patients received placebo once daily for days 1 to 7 and 20 mg lercanidipine for days 8-14 for non-dialysis patients or for days 8-15 for dialysis patients (11). Patients were seven men and seven women, mean age 57 ± 14 years, weight 65 ± 15 kg, height 164 ± 13 cm, who had chronic renal failure and were suffering from mild to moderate essential hypertension. Thirteen patients completed the study. They were divided into three categories: (a) creatinine clearance 30-59 ml/min; (b) creatinine clearance 10-29 ml/min, not in dialysis; and (c) those undergoing regular dialysis. The pharmacokinetic parameters for S(+)-lercanidipine are shown in Table 11. These data suggest that accumulation may not be a problem in patients with mild to moderate renal dysfunction but is almost certain to occur in patients with severe renal dysfunction, for whom a reduction in the starting dose and caution in dose incrementation are suggested. Plasma levels of S(+)-lercanidipine are shown in Fig. 10.TABLE 11: Mean values (±SD) of S(+)-lercanidipine enantiomer pharmacokinetic parameters in hypertensive patients (n = 13) with different grades of renal insufficiency after single 20-mg oral doses of lercanidipine HCl tabletsFIG. 10.: S(+)-lercanidipine mean plasma levels after repeated oral administration of 20 mg lercanidipine HCI daily for 7 days to mild or moderately hypertensive patients with renal failure.HEPATIC DISEASE IN CIRRHOTIC PATIENTS Twelve patients, six men and six women, mean age 54 ± 10 years, weight 65 ± 12 kg, height 162 ± 8 cm, with cirrhosis (confirmed by ultrasound and histology to belong to Child-Pugh class A) received a single oral dose of 10 mg lercanidipine HCl in tablet form (12). The data obtained are shown in Table 12. Statistical analysis of the results (ANOVA and Tukey's student's range test on 90% CI of differences between means of the parameters) showed that there was no significant difference in Cmax and AUC in cirrhotic patients compared to hypertensive patients.TABLE 12: Mean values (±SD) of lercanidipine (lerc) enantiomer pharmacokinetic parameters in cirrhotic patients (n = 12) or in mild to moderately hypertensive patients (n = 12) after a single 10 mg oral dose of lercanidipine HCl tabletsDISEASE, AGE, AND STEREOSELECTIVITY The ratio of Cmax and AUC(0-t) for S(+)/R(−) in various groups is shown in Table 13. These data suggest that the relative profile of the two enantiomers is reasonably constant across all groups at all time points except for the renal patients, who experienced greater exposure to the more active S(+) enantiomer.TABLE 13: S(+)-lercanidipine/R(−)-lercanidipine AUC and Cmax ratios in different groups of subjects after lercanidipine HCl administrationFigures 11 and 12 show the lercanidipine enantiomer plasma concentrations in hypertensive patients after 10 mg or 20 mg lercanidipine HCl in tablet form.FIG. 11.: Lercanidipine enantiomer mean plasma levels after repeated oral administration of 10 mg lercanidipine HCI daily for 7 days in mild to moderately hypertensive patients (n = 12).FIG. 12.: Lercanidipine enantiomer mean plasma levels after repeated oral administration of 20 mg lercanidipine HCI daily for 7 days in mild to moderately hypertensive patients (n = 12).INTERACTION WITH DRUGS Cimetidine Twelve healthy male volunteers, mean age 26 ± 4 years, weight 72 ± 4 kg, height 180 ± 5 cm, were enrolled in an open two-way study. Each volunteer received a single oral dose of 20 mg lercanidipine HCl in tablet form on day 1. This was followed by treatment with 400 mg cimetidine b.i.d. for 14 days. On day 15 the volunteers received a single oral dose of 20 mg lercanidipine HCl 1 h after the morning dose of cimetidine (13). The main pharmacokinetic parameters of lercanidipine before and after 14 days of treatment with 400 mg cimetidine b.i.d. were not significantly different, as shown in Table 14. The plasma concentration profiles are shown in Fig. 13. Treatment with cimetidine did not alter the enantiomeric ratio. Because no significant effects were observed, co-administration of lercanidipine and cimetidine does not require dosage adjustment.TABLE 14: Mean values (±SD) of lercanidipine pharmacokinetic parameters (20-mg single oral dose) in healthy male volunteers (n = 12) before and after 14 days of treatment with 400 mg cimetidine b.i.d.FIG. 13.: Lercanidipine plasma levels in male healthy volunteers after a 20-mg single oral dose of lercanidipine HCI before (day 1) and after (day 15) 400 mg of cimetidine b.i.d. for 2 weeks. Mean values (n = 12).Digoxin Twelve female patients with cardiovascular disease, with or without heart failure (CHF) and already in therapy with cardiac glycoside, were enrolled in the study. Eleven patients, mean age 60 ± 10 years, weight 69 ± 14 kg. height 160 ± 5 cm, completed the study (14). Of these. 10 were receiving β-methyldigoxin and one digoxin. Confirmation that patients had reached steady-state was ensured by measurement of the plasma levels of the glycoside before the study began. Patients subsequently received 7 days of placebo or 20 mg lercanidipine HCl tablets, and plasma levels of the glycoside and lercanidipine were measured. An ECG was also performed. Table 15 shows the data on the concentrations of methyldigoxin and digoxin in 10 patients who were receiving 0.1 mg methyldigoxin daily. No significant modifications in plasma levels of cardiac glycosides and no toxic effects were observed. Plasma levels of lercanidipine on day 7 of lercanidipine HCl therapy were not significantly different from those observed in mild to moderately hypertensive patients (6), demonstrating a lack of effect of methyldigoxin on lercanidipine disposition. Similarly no interaction was observed in the one patient who was receiving digoxin 0.125 mg daily.TABLE 15: Mean values (±SD) of cardiac glycoside parameters and of PR and QRS intervals in patients under chronic treatment with β-methyldigoxin, before or after 7 days of placebo or 20 mg/day lercanidipine HCl tablets