Influence of chronic kidney disease on enantioselective pharmacokinetic-pharmacodynamic lercanidipine-carvedilol interaction

EB Coelho1, EH Schaab2, MP Marques2, M Dantas1, CE Paiva1, VL Lanchote0. 1Faculdade de Medicina de Ribeirão Preto Universidade de São Paulo, Clinica Medica, Brazil, 2Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Universidade de São Paulo, Análises Clínicas, Toxicológicas e Bromatológicas, Brazil

Patients with chronic kidney disease (CKD) may have some modification on proteins linked to transport and metabolism of drugs due to accumulation of uremic toxins. Carvedilol is a chiral adrenergic blocker drug administered as a racemic mixture for the treatment of cardiovascular diseases. The non-selective beta-blocking activity is attributed to (S)-(-) enantiomer, whereas both enantiomers exhibit equipotent alfa1-blocking activity. Additionally, (R)-(+)-carvedilol presents higher plasma concentrations, bioavailability and protein binding. Carvedilol has been found to be a substrate and an inhibitor of P-glycoprotein (Pgp). Lercanidipine is a substrate of CYP3A4, but there is no data related to its activity on Pgp. The present study aims to evaluate the influence of CKD stage 3 and 4 (NFK-KDOQI) on carvedilol-lercanidipine enantiomers interaction. Hypertensive patients with CKD (n=8 with creatinine clearance ranging from 20-59 ml/min) and control hypertensive patients with normal kidney function (n=8, creatinine clearance>90ml/min), characterized as extensive metabolizers to CYP2D6 and CYP3A4 were included in an open label, randomized, crossover study with "wash-out" period between treatments of one week. Subjects received a single oral dose of racemic carvedilol (25 mg) or a single oral dose of racemic lercanidipine (20mg) or an association of both drugs. Serial blood samples were collected from 0 to 32 h, carvedilol and lercanidipine enantiomers were analyzed by LC-MS-MS on a Chirobiotic®V column and pharmacokinetic parameters were evaluated using a bicompartment model. Change in exercise-induced heart rate (2 min of isometric exercise using a handgrip dynamometer at 30% of maximal voluntary contraction) measured on each time of blood sampling was used as pharmacodynamic parameter. The inhibitory effect sigmoid Emax was used as PK-PD model (WinNonlin 4.0). The pharmacokinetic of carvedilol in single dose or associated with lercanidipine was enantioselective with accumulation of (R)-(+)-carvedilol in both experimental groups. The administration of lercanidipine increased the area under the curve (190.6 vs 98.9 ng.h/mL, P<0.05) and reduced the apparent clearance of carvedilol (65.7 vs 51.9 L/h, P<0.05) only on CKD group. However, there was not statistical differences on pharmacokinetic parameters of carvedilol when compared CRK with control group. The association of lercanidipine did not change the PK-PD of carvedilol in both experimental groups. However, CKD showed higher carvedilol ECe50 values compared with control (11.9 vs 7.8 ng/mL, P<0.05). Regarding pharmacokinetic disposition of lercanidipine, the association of carvedilol reduced the apparent total clearance of (S)-lercanidipine only on CKD (656.2 vs 1102.6 L/h, P<0.05), but there was not differences on pharmacokinetic parameters of lercanidipine between control and CKD group. In conclusion, our data suggest an enantioselective lercanidipine Pgp-inhibition, probably due to a drug-disease interaction. In CKD, higher doses of carvedilol could be necessary to reach the same vasodilator effect observed in control with normal kidney function due to a loss of potency of carvedilol observed in CKD patients. Studies of drug-drug interaction may have the results marked changed by CKD influence. Thus, such kind of study might be done using CKD patients rather than healthy controls.