Christine E. Staatz (1), Troels K. Bergmann (1,2), Katherine A. Barraclough (3), Nicole M. Isbel (3), Stefanie Hennig (1).
(1) School of Pharmacy, University of Queensland, Brisbane, Australia; (2) Department of Medicine, Aabenraa Hospital, Aabenraa, Denmark; (3) Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia
Objectives: 1) To develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients; 2) to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype based initial dosing to standard per-kilogram based initial dosing of tacrolimus; and 3) to predict the best starting regimen of tacrolimus based on patient genotype to achieve a trough concentration between 6 and10 ug/L by day 5 post-transplant.
Methods: Data from 173 adult kidney transplant recipients at the Princess Alexandra Hospital in Brisbane, Australia were analysed. In total, 1554 tacrolimus concentration-time measurements taken on 338 occasions were available along with patient covariate information. Population pharmacokinetic modelling was performed using NONMEM 7.2 and the FOCE+I estimation method. Starting dose regimens were compared by simulating tacrolimus trough concentrations in all patients using the final model with population parameters fixed at final estimates.
Results: A 2-compartment model with first order absorption after a lag time and first order elimination described the data well. Patient CYP3A5 genotype (rs776746), weight, haematocrit and post-operative day were identified as significant covariates effecting tacrolimus apparent clearance (CL/F). Higher CL/F was identified in CYP3A5 *1 allele carriers, heavier patients, patients with low haematocrit and those in the immediate post-transplant period. Typical population estimates for tacrolimus CL/F in CYP3A5 *1 allele carriers and non-carriers were 42.7 L/h and 24.8 L/h respectively. In patients carrying the CYP3A5*1 allele, standard 0.075 mg/kg twice daily initial dosing of tacrolimus was too low with approximately 65% of simulated subjects achieving trough concentrations below 6 µg/L at day 5 post-transplant.
Conclusions: To reduce the risk of under immunosuppression in the immediate post-transplant period carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting regimen of 0.115 mg/kg twice daily.
Reference: PAGE 22 (2013) Abstr 2736 [www.page-meeting.org/?abstract=2736]
Poster: Other Drug/Disease Modelling