Population pharmacokinetics of tacrolimus in paediatric heamatopeitic stem cell transplantation
Johan E Wallin (1), Lena E Friberg (1), Christine E Staatz (2)
(1)Division of Pharmacokinetics and Drug Therapy, Biomedical Centre, Uppsala University, Uppsala, Sweden (2) School of Pharmacy, University of Queensland, Brisbane, Australia.
Objectives: Tacrolimus is emerging as a valuable immunosuppressant option in the prevention of graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Little data is available on the pharmacokinetics of tacrolimus in paediatric BMT recipients, with only one previous investigation involving 7 subjects . The aim of this study was to evaluate the population pharmacokinetics of tacrolimus in paediatric BMT recipients in the first year post-transplant and to identify factors that may explain pharmacokinetic variability.
Methods: Data were collected retrospectively from the medical records of 22 children transplanted between 1997 and 2007 at Queen Silvia’s Children’s Hospital in Gothenburg, Sweden. Population pharmacokinetic analysis was performed using NONMEM version 6 . Maximum likelihood estimates were sought for tacrolimus clearance (CL), volume of distribution (V) and bioavailability (F). V and CL was allometrically scaled to lean body weight. A previously suggested model with a time-dependent increase in tacrolimus apparent clearance (CL/F) [3,4] was compared to a simpler one- or two- compartment model. A step-wise covariate search with a significance criteria of p<0.01 was performed . Covariates screened for influence on the pharmacokinetic parameters were liver function tests (AST, ALT, GGT, ALP), bilirubin, albumin, creatinine clearance, sex, age and post-operative day.
Results: All subjects received tacrolimus initially as a continuous intravenous infusion at 0.03 mg/kg/day, starting approximately two days before transplantation. Patients were converted to oral tacrolimus therapy two to three weeks after transplantation, with an initial oral dose approximately four times the intravenous dose, divided into twice daily administration. A one-compartment model with first order absorption and elimination was considered optimal for modelling the data. Under the final base model mean CL was 0.140 L/h/kg0.75, V was 12.7 L/kg and F was 13%. Inter-individual variability in CL, V and F was 60%, 70% and 54% respectively. Covariate analysis suggested tacrolimus CL positively correlated with creatinine clearance and GGT. Tacrolimus F decrease with time post-transplant.
Conclusions: Tacrolimus CL was similar to that estimated in adult BMT recipients when scaled to 75kg/170cm , 3.56 L/h compared to 5.22 L/h in adults. F was notably lower, approximately half of the 28% reported in adults . This may be attributed to the use of a paediatric formulation in this study. Decreasing F with time post-transplant found in this study might be explained by the occurrence of chronic GVHD in these patients over time. Pharmacokinetic parameters obtained in this study may assist physicians in making individualized dosage decisions with regards to tacrolimus in paediatric BMT recipients.
 Mehta P, Beltz S, Kedar A, et al. Bone Marrow Transplantation 1999; 24: 1323-1327.
 Beal SL, Sheiner LB. NONMEM users guide (NONMEM project group, University of California, San Fransisco, CA, 1992)
 Antignac M, Barrou B, Farinotti R, et al. Br J Clin Pharmacol 2007; 64: 750-757.
 Antignac M, Hulot JS, Boleslawski E, et al. Eur J Clin Pharmacol 2005; 61: 409-416.
 Lindbom L, Pihlgren P, Jonsson EN. Comput Methods Programs Biomed 2005; 79: 241-57.
 Jacobson P, Ng J, Ratanatharathorn V, et al. Bone Marrow Transplant 2001; 28: 753-758.