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

被引:43
作者
Albers, Stefanie [1 ]
Meibohm, Bernd [2 ]
Mir, Thomas S. [3 ]
Laeer, Stephanie [1 ]
机构
[1] Univ Dusseldorf, D-40225 Dusseldorf, Germany
[2] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Memphis, TN 38163 USA
[3] Univ Hamburg, Dept Paediat Cardiol, Hamburg, Germany
关键词
carvedilol; computer simulation; paediatrics; pharmacokinetics;
D O I
10.1111/j.1365-2125.2007.03046.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:511 / 522
页数:12
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