Population Pharmacokinetics and Dose Simulation of Carvedilol in Pediatric Patients with Congestive Heart Failure
S. Albers (1), B. Meibohm (2), J. Barrett (3), TS. Mir (4), S. Laer (1)
(1) Clinical Pharmacy and Pharmacotherapy, University of Duesseldorf, Germany; (2) Department of Pharmaceutical Sciences, University of Tennessee, Memphis, USA, (3) Childrens Hospital of Philadelphia, Philadelphia, USA, (4) Department of Pediatric Cardiology, University of Hamburg, Germany
Objectives: In-silico tools like population pharmacokinetic (Pop-PK) modeling and simulation play a pivotal role in developing safe and effective dosing strategies especially for pediatric patients. Therefore, the aim of our work was to investigate the ontogeny of carvedilol pharmacokinetics in pediatric patients by Pop-PK analysis. Dose simulations were performed to investigate the carvedilol dosing strategy for pediatric patients. The integration of these dosing regimens into clinical studies might increase the probability of success in future randomized controlled clinical studies aiming at efficacy.
Methods: Data were derived from a prospective, open-label study of carvedilol for the therapy of pediatric patients with congestive heart failure. Up to 13 plasma concentrations were determined from each patient during one dosing interval after 0.09 mg/kg QD and 0.35 mg/kg BID, respectively, using a validated HPLC-assay. Total plasma concentrations were analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population model was further used for simulations of different daily doses and dosing intervals. Target parameter for the simulations was the area under the plasma concentration time curve (AUC) as a measure of drug exposure.
Results: 480 carvedilol plasma concentrations of 41 patients (0.1 - 19.3 years; median 3.5) were included in the analysis. Carvedilol pharmacokinetics were best described by a two-compartment model with first order absorption and absorption lag. Allometric weight normalization was used for clearances and volume of distribution parameters. Additionally, a significant influence of age on clearance (CL) and central volume of distribution (V2) was found:
CL [L/h] = 38.1*((weight [kg]/13)**0.75)-((age [years]/3.5)**2.7)
V2 [L] = 22.0*(weight [kg]/13)*(1-(0.13*age [years]/3.5))
Dose simulations revealed that for infants (28 days - 23 months), children (2 - 11 years) and adolescents (12 - 15 years) daily doses of 3, 2 and 1 mg/kg, administered in two or three doses were necessary to reach an exposure (AUC) comparable to adults receiving 0.7 mg/kg/day.
Conclusions: Younger patients have to be treated with higher doses of carvedilol to reach the same exposure as adults. These results have to be considered for further randomized controlled trials investigating the efficacy of carvedilol in order to avoid ineffective drug exposures.