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Developmental pharmacokinetics of ciclosporin – a population pharmacokinetic study in paediatric renal transplant candidates
Author(s) -
Fanta S.,
Jönsson S.,
Backman J. T.,
Karlsson M. O.,
Hoppu K.
Publication year - 2007
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.03003.x
Subject(s) - ciclosporin , pharmacokinetics , bioavailability , population , nonmem , volume of distribution , medicine , dosing , physiology , urology , transplantation , endocrinology , pharmacology , environmental health
What is already known about this subject • Ciclosporin is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. • It is likely that the inter‐ and intraindividual variability in ciclosporin pharmacokinetics and dose requirements is even larger in children than in adults as a result of variation in biological maturation status. • However, data on the developmental pharmacokinetics of ciclosporin, as well as other CYP3A4 substrate drugs, in children are scarce. What this study adds • Adult CYP3A4 activity seems to be reached by the age of 6–12 months, and allometrically scaled body weight is a good predictor of the hepatic clearance of ciclosporin, a CYP3A4 substrate. • Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. • These conclusions were reached using a robust modelling approach (NONMEM) with rich paediatric pharmacokinetic data collected after full i.v. and p.o. profiles. Aims To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin. Methods Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg −1 ) and orally (10 mg kg −1 ) on separate occasions followed by blood sampling for 24 h. Results A three‐compartment model with first‐order absorption without lag‐time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume ( V ) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V . The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age‐related changes in oral bioavailability or in BW‐normalized V were seen. The BW‐normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW 3/4 ) removed its relationship to age. Conclusion The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.