Tacrolimus Population Pharmacokinetic-Pharmacogenetic Analysis and Bayesian Estimation in Renal Transplant Recipients

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients. Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12

Drug-resistant cytomegalovirus in transplant recipients: a French cohort study.

International audienceObjectives Cytomegalovirus (CMV) drug resistance is a therapeutic challenge in the transplant setting. No longitudinal cohort studies of CMV resistance in a real-life setting have been published in the valganciclovir era. We report findings for a French multicentre prospective cohort of 346 patients enrolled at initial diagnosis of CMV infection (clinical trial registered at clinicaltrials.gov: NCT01008540). Patients and methods Patients were monitored for detection of CMV infection for ≥2 years. Real-time detection of resistance by UL97 and UL54 gene sequencing and antiviral phenotyping was performed if viral replication persisted for >21 days of appropriate antiviral treatment. Plasma ganciclovir assays were performed when resistance was suspected. Results Resistance was suspected in 37 (10.7%) patients; 18/37 (5.2% of the cohort) had virological resistance, associated with poorer outcome. Most cases involved single UL97 mutations, but four cases of multidrug resistance were due to UL54 mutations. In solid organ transplant recipients, resistance occurred mainly during primary CMV infection (odds ratio 8.78), but also in two CMV-seropositive kidney recipients. Neither CMV prophylaxis nor antilymphocyte antibody administration was associated with virological resistance. Conclusions These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure

Genome-wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls, on Illumina 2.5 M arrays. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant SNPs from the discovery cohort. In the discovery cohort, we found 5 candidate loci tagged by a number of contiguous SNPs (>5) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signalling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium. This article is protected by copyright. All rights reserved