Explaining Variability in Tacrolimus Pharmacokinetics to Optimize Early Exposure in Adult Kidney Transplant Recipients

Abstract

To prevent acute rejection episodes, it is important to reach adequate tacrolimus (TRL) exposure early after kidney transplantation. With a better understanding of the high variability in the pharmacokinetics of TRL, the starting dose can be individualized, resulting in a reduction in dose adjustments to obtain the target exposure. A population pharmacokinetic analysis was performed to estimate the effects of demographic factors, hematocrit, serum albumin concentration, prednisolone dose, TRL dose interval, polymorphisms in genes coding for ABCB1, CYP3A5, CYP3A4, and the pregnane X receptor on TRL pharmacokinetics. Pharmacokinetic data were prospectively obtained in 31 de novo kidney transplant patients randomized to receive TRL once or twice daily, and subsequently, the data were analyzed by means of nonlinear mixed-effects modeling. TRL clearance was 1.5-fold higher for patients with the CYP3A5*1/*3 genotype compared with the CYP3A5*3/*3 genotype (5.5 +/- 0.5 L/h versus 3.7 +/- 0.3 L/h, respectively). This factor explained 30% of the interindividual variability in apparent clearance (exposure). Also, a relationship between the pregnane X receptor A+7635G genotype and TRL clearance was identified with a clearance of 3.9 +/- 0.3 L/h in the A allele carriers versus 5.4 +/- 0.6 L/h in the GG genotype. Finally, a concomitant prednisolone dose of more than 10 mg/d increased the TRL apparent clearance by 15%. In contrast, body weight was not related to TRL clearance in this population. Because patients are typically dosed per kilogram body weight, this might result in underexposure and overexposure in patients, with a low and high body weight, respectively. This integrated analysis shows that adult renal transplant recipients with the CYP3A5*1/*3 genotype require a 1.5 times higher, fixed, starting dose compared with CYP3A5*3/*3 to reach the predefined target exposure early after transplantation.

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…Differences in the distribution of PXR SNPs were found when comparing the Han Chinese of South China and Caucasian Americans [31] . PXR -25385C>T, an SNP located in the PXR promoter and found to be correlated with CYP3A4 phenotype, was identified as a significant covariate for apparent oral clearance (CL/F) of tacrolimus by Benkali et al [32] , but this result could not be replicated in another study [33] . Cytochrome P450 oxidoreductase (POR) is known as the obligatory electron donor in the metabolism of drugs by CYP enzymes in humans, and the correlation between POR genetic polymorphisms and CYP-catalyzed drug metabolism has become a research hot spot.…”

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

“…In addition, tacrolimus is also highly metabolized by CYP3A5. 5 The peri-transplant period is characterized by the administration of numerous drugs that can affect the cytochrome P450 system and alter tacrolimus clearance. Population pharmacokinetic studies in HSCT recipients have shown that liver or kidney impairment can result in decreased tacrolimus clearance and increased blood tacrolimus concentrations.…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…In fact, in this multi-center randomized controlled trial, patients receiving tacrolimus daily dose according to their CYP3A5 genotype, achieved the target concentration more rapidly with lesser dose modification and in an higher percentage ( >75%) when compared to those in whom tacrolimus was managed with a concentrationcontrol strategy [21]. ABCB1 polymorphisms do not seem to influence tacrolimus pharmacokinetic and research into this association has yielded mixed results [22,23]. Nevertheless, in our series we observed a significant reduction in tacrolimus concentration and dose-adjusted tacrolimus concentrations in the early post-transplant period for the TT polymorphism of C1236T; this suggests that there is higher metabolism of the drug in subjects with this genotype [24].…”