Population Pharmacokinetics of Cyclosporine in Paediatric Renal Transplant Recipients
S. Fanta(1), S. J÷nsson(2), M.O. Karlsson(3), C. Holmberg(4), K. Hoppu(1), J.T. Backman(1)
(1) Department of Clinical Pharmacology, Helsinki University Central Hospital, Helsinki, Finland; (2) Medical Products Agency, Uppsala, Sweden; (3) Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden; (4) Paediatric Nephrology and Transplantation, Hospital for Children and Adolescents, Helsinki, Finland
Objectives: Cyclosporine is a drug with a narrow therapeutic index and large interindividual variability in pharmacokinetics. Therefore, after renal transplantation, the individual dose is established by monitoring the cyclosporine exposure, mainly by trough (C0) based monitoring. This study aimed to characterize the effects of demographic and clinical covariates on cyclosporine pharmacokinetics in renal transplanted children in order to improve the possibilities of individualization of cyclosporine dosing.
Methods: Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 renal transplanted children (age: 0.36-20.2 years). Before transplantation, cyclosporine was given i.v. (3 mg/kg) and p.o. (10 mg/kg) on separate occasions followed by blood sampling for 24 h. After transplantation, cyclosporine was given i.v. immediately after transplantation and p.o. thereafter, with individually adjusted doses. Blood sampling was carried out at trough (C0) and occasionally also two hours after dosing (C2). The follow-up time after transplantation was 0-16.2 years.
Results: A three-compartment model with first order absorption best described the pharmacokinetics of cyclosporine. The typical value of clearance (for a typical 13 kg patient) was 5.8 L/h, the volume of distribution at steady state was 26 L, and the oral bioavailability (F) before transplantation was 0.31. The F changed with time after transplantation. This effect was modelled as a Bateman function. For the average patient, the maximal F was 0.55 and was reached one month after transplantation. Afterwards the F decreased to reach the pretransplantatation value of 0.31 in one year after transplantation. In addition, the patients who were dosed twice daily had constantly a 24% higher F than patients who were dosed thrice daily. With increasing body weight and serum creatinine, cyclosporine clearance (CL) and volume (V) parameters increased. With increasing plasma cholesterol and haematocrit, CL and V parameters decreased. The interoccasion variability was estimated to be about the same size as the interindividual variability for both CL (13% vs. 11%, CV%) and F (0.07 vs. 0.06, SD).
Conclusions: The bioavailability of cyclosporine changes dramatically in the first year after transplantation. The high interoccasion variability in pharmacokinetics makes individualization of cyclosporine dosing difficult and is likely to reduce the value of sparsely occurring therapeutic drug monitoring.