Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure

TY - JOUR

T1 - Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure

AU - Albers, Stefanie

AU - Meibohm, Bernd

AU - Mir, Thomas S

AU - Läer, Stephanie

PY - 2008/4

Y1 - 2008/4

N2 - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial. * Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous. * Further trials are necessary to establish carvedilol for paediatric patients with CHF.WHAT THIS STUDY ADDS: * Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient. * Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight. * Simulations revealed that an age-adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.AIMS: To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age-appropriate carvedilol dosing strategy for paediatric patients.METHODS: Data were derived from a prospective, nonplacebo-controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.RESULTS: Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1-19.3 years; median 3.5) were included in the analysis. A two-compartment model with first-order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight-adjusted clearance was highest for the younger patients with 2.7 l h(-1) kg(-1) for a 1-year-old patient compared with 0.7 l h(-1) kg(-1) for a 19.3-year-old patient. Dose simulations revealed that the area under the plasma concentration-time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2-11 years) and adolescents (12-15 years) daily doses of 3, 2 and 1 mg kg(-1), administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg(-1) day(-1).CONCLUSION: The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.

AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Applying in silico tools such as population pharmacokinetic analysis and simulation will help to find adequate dosing strategies and increase the probability of success for a randomized controlled trial. * Up to now, for carvedilol in paediatric patients with congestive heart failure (CHF) the dose has been linearly extrapolated from adults, but the results with this dosing strategy are ambiguous. * Further trials are necessary to establish carvedilol for paediatric patients with CHF.WHAT THIS STUDY ADDS: * Carvedilol pharmacokinetics in paediatric patients with CHF depends on the weight and age of the patient. * Therefore, the drug exposure differs substantially between patients of different ages receiving the same dose with respect to body weight. * Simulations revealed that an age-adjusted carvedilol dosing strategy with higher doses for younger patients with respect to body weight is preferable to a uniform one.AIMS: To investigate the ontogeny of carvedilol pharmacokinetics and to develop an age-appropriate carvedilol dosing strategy for paediatric patients.METHODS: Data were derived from a prospective, nonplacebo-controlled study of carvedilol for the treatment of paediatric patients with congestive heart failure and analysed using a nonlinear mixed-effects modelling approach (NONMEM, Version V 1.1). The population pharmacokinetic model was further utilized for simulations of different carvedilol dosing strategies.RESULTS: Four hundred and eighty carvedilol plasma concentrations of 41 patients (0.1-19.3 years; median 3.5) were included in the analysis. A two-compartment model with first-order absorption and absorption lag served as structural model. Weight and age were the most important covariates for carvedilol pharmacokinetics. The weight-adjusted clearance was highest for the younger patients with 2.7 l h(-1) kg(-1) for a 1-year-old patient compared with 0.7 l h(-1) kg(-1) for a 19.3-year-old patient. Dose simulations revealed that the area under the plasma concentration-time curve (AUC) as a measure of drug exposure increased with age despite constant doses with respect to body weight. For infants (28 days to 23 months), children (2-11 years) and adolescents (12-15 years) daily doses of 3, 2 and 1 mg kg(-1), administered in two or three discrete doses, were necessary to reach an exposure comparable to adults receiving 0.7 mg kg(-1) day(-1).CONCLUSION: The ontogeny of carvedilol pharmacokinetics in paediatric patients depends on age and weight. Dose simulations revealed that younger patients have to be treated with higher doses with respect to body weight to reach the same exposure as adults.

KW - Adolescent

KW - Adrenergic alpha-Antagonists/administration & dosage

KW - Adult

KW - Body Weight/drug effects

KW - Carbazoles/administration & dosage

KW - Carvedilol

KW - Child

KW - Child, Preschool

KW - Computer Simulation

KW - Dose-Response Relationship, Drug

KW - Female

KW - Germany/epidemiology

KW - Heart Failure/drug therapy

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Models, Theoretical

KW - Propanolamines/administration & dosage

KW - Treatment Outcome

U2 - 10.1111/j.1365-2125.2007.03046.x

DO - 10.1111/j.1365-2125.2007.03046.x

M3 - SCORING: Journal article

C2 - 17995971

VL - 65

SP - 511

EP - 522

JO - BRIT J CLIN PHARMACO

JF - BRIT J CLIN PHARMACO

SN - 0306-5251

IS - 4

M1 - 4

ER -