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

Stefanie Albers, Bernd Meibohm, Thomas S. Mir, Stephanie Läer

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)511-522
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume65
Issue number4
DOIs
StatePublished - Apr 1 2008

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Heart Failure
Pharmacokinetics
Pediatrics
Population
Weights and Measures
Body Weight
carvedilol
Structural Models
Area Under Curve
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure. / Albers, Stefanie; Meibohm, Bernd; Mir, Thomas S.; Läer, Stephanie.

In: British Journal of Clinical Pharmacology, Vol. 65, No. 4, 01.04.2008, p. 511-522.

Research output: Contribution to journalArticle

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