Optimizing Calcineurin Inhibitor Exposure In De Novo Kidney Transplant Recipients
Rogier R. Press
Leiden University Medical Center
Objectives: The calcineurin inhibitors (CNI), tacrolimus (TRL) and ciclosporin A (CsA), display acute and chronic toxicity. Their use in the early post transplant period is shifting towards minimization in order to limit toxicity. The balance between efficacy and toxicity of these drugs is reflected by their (blood)exposure which varies considerably among individuals. Insight in the sources of variability in pharmacokinetics (PK) can be used for individualization of CNI therapy in kidney transplant recipients and thus tailor immunosuppressive therapy. Therefore, this study aimed at a combined analysis of a series of genetic and non-genetic factors that may explain intra-and interindividual variability in PK.
Methods: PK data were obtained from de novo kidney transplant patients (n=64) receiving either once or twice daily CsA or TRL with a follow up of one year. PK was sampled up to 12 hours after drug administration and on multiple occasions (10 per patient). The population PK analyses were performed with Non-Linear-Mixed-Effects-Modelling and were directed towards determination of the effects of the following genetic and non-genetic factors on CNI PK: hematocrit, serum albumin concentration, prednisolone dose, once or twice daily dosing, demographic factors and genetic factors such as polymorphisms in ABCB1 (T3435C,G2677T,C1236T,T-129C)), CYP3A5(*3 and *6), CYP3A4*1B and the nuclear factor Pregnane-X-Receptor (PXR)(C-25385T,A-24381C,G-24113A,A+252G,A+7635G).
Results: Two significant covariates were identified for CsA explaining 8% of the observed variability in CsA apparent clearance (decreasing from 25% to 17%) of which bodyweight was the most important one. Clearance increased with 0.1 L/h/per kg bodyweight relative to the clearance of a typical subject (range 8 to 25 L/h) within the bodyweight range (49 to 119 kg). A prednisolone dose greater than 20 mg increased CsA clearance with 23%. The TRL analysis revealed three significant factors of which CYP3A5 was the most important and explained 11% of the variability in TRL clearance. TRL clearance was 3.7±0.7L/h versus 5.9±1.1L/h for the genotypes CYP3A5*3/*3 and CYP3A5*1/*3 respectively. The second most important factor was a polymorphism in PXR7635, which explained 3.5% of the variability in clearance: TRL clearance was 3.5±0.7L/h in the PXR CT/TT phenotype versus 4.9±1.0L/h in the CC phenotype. Finally, a concomitant dose of prednisolone greater than 10 mg increased TRL apparent clearance by 17%. TRL exposure in terms of apparent clearance did not correlate with bodyweight.
Conclusions: The results of the present study indicate that the CsA dose depends on bodyweight, whereas the initial TRL dose for immunosuppression in adult kidney transplant recipients should be based on genotype rather than on bodyweight. Patients with the CYP3A5*1/*3 genotype need a 1.6 times higher initial TRL dose compared to CYP3A5*3/*3 carriers to reach target exposure.