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Population pharmacokinetics of carvedilol in pediatric patients with congestive heart failure
Author(s) -
Laer S.,
Albers S.,
Gupta M.,
Mir T. S.,
Meibohm B.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.229
Subject(s) - carvedilol , pharmacokinetics , dosing , medicine , heart failure , clinical pharmacology , volume of distribution , population , pharmacology , population pharmacokinetics , environmental health
Background/Aim Population pharmacokinetic analysis (POP‐PK) plays a pivotal role in developing dosing strategies as well as quantifying and explaining pharmacokinetic variability. The aim of our study was to characterize the ontogeny on clinical PK of carvedilol (C) in pediatric patients with congestive heart failure using POP‐PK. Methods Nonlinear mixed‐effects modeling including covariate analysis was used to characterize the PK of C in pediatric patients. Up to 13 C plasma concentrations were determined from each patient during one dosing interval using a validated HPLC‐assay. 41 Caucasians (median age 3.53 yrs[0.07–19]) provided 524 C concentrations for PK analysis while receiving oral C doses of 0.09 to 0.7 mg/kg per day for the treatment of congestive heart failure. Results PK of C was best described by a two‐compartment model with first‐order absorption. Allometric weight normalization (WT in kg) was used for clearance (CL, Q) and volume of distribution parameters (Vc, Vss): CL[L/hr]=136•(WT/70kg) (0.75) ; Vss[L]=496•(WT/70kg). CL was additionally modified by age in children older than 5 yrs: CL[L/hr]=(136−(6.23•(Age−5yrs)))•(WT/70kg) (0.75)Conclusion The identified developmental changes in the clinical pharmacology of C suggest a process which peaks at about 5 years of age and decreases until adolescence. This should be implemented into dosing strategies but also the underlying mechanism of action should be explored. Clinical Pharmacology & Therapeutics (2005) 77 , P88–P88; doi: 10.1016/j.clpt.2004.12.229