<i><scp>CYP</scp>3A</i> pharmacogenetics and tacrolimus disposition in adult heart transplant recipients

Deininger, Kimberly M.; Vu, Anh; Page, Robert L.; Ambardekar, Amrut V.; Lindenfeld, JoAnn; Aquilante, Christina L.

doi:10.1111/ctr.12790

Cited by 22 publications

(24 citation statements)

References 42 publications

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“…Consistent with what has been reported in solid organ transplant populations, we found that recipients with rapid-metabolizing CYP3A genotypes require higher doses of tacrolimus to maintain therapeutic drug levels compared to other genotypes. 7,11,[28][29][30][31][32][33][34][35] Rapid-metabolizing genotypes were associated with increased time to therapeutic tacrolimus level and decreased days in therapeutic range. Additionally, we found decreased rates of acute cellular rejection in lung allograft recipients with ABCB1 poor efflux activity.…”

Section: Discussionmentioning

confidence: 99%

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Calabrese

Florez

Dewey

et al. 2018

Clinical Transplantation

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Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Calabrese

Florez

Dewey

et al. 2018

Clinical Transplantation

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“…patients, but the effect was largely driven by CYP3A5*3. 29 Genetic polymorphisms of metabolising enzymes and transport proteins should be investigated for the individualisation of tacrolimus dosing for cardiac transplant patients in further prospective studies. In summary, the well-known covariates POD, WZ capsules and BW were successfully identified as the important factors affecting tacrolimus CL/F and V/F in heart transplant patients.…”

Section: What This Paper Addsmentioning

confidence: 99%

Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients

et al. 2019

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Objective Usage of tacrolimus is complicated by its narrow therapeutic index and wide between-and withinsubject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on the disposition of tacrolimus in the early phase after cardiac transplantation using a population pharmacokinetic method, and provide information for the individualisation of drug dosing in the clinical setting. Methods Routine therapeutic drug monitoring concentrations (897 observations) were retrospectively collected from 146 hospitalised patients. One compartment model with first-order absorption (absorption rate constant K a was fixed as 4.48/ hour) was employed to establish the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Various demographic parameters, postoperative day and concomitant medications influencing drug clearance and distribution volume were investigated in this study. Bootstrap and predictioncorrected visual predictive check were employed to validate the final model. With the goal of tacrolimus trough concentrations within the therapeutic window, simulation was performed. results Pharmacokinetic parameter population typical estimates for clearance (CL/F) and apparent distribution volume (V/F) were 14.23 L/hour and 760.80 L, respectively. Postoperative day and co-administration of Wuzhi capsules were identified as important factors affecting CL/F. Total body weight was significantly associated with the V/F. Results of model evaluation indicated a good stable and precise performance of the final model. Based on the simulation results, a simpletouse dosage regimen table to guide clinicians with drug dosing was created. Conclusion The final population model could provide information for the individualised dosing of tacrolimus for cardiac transplant recipients.

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“…In addition, many reports suggest that CYP3A5 is related to the mean concentration/dose ratio (C/D) of CNIs. Some researchers have reported that nonexpressers exhibit greater renal CNI metabolism; thus, even though nonexpressers require a lower initial dose, they have higher CNI blood concentrations and C/D values [51][52][53][54][55]. These results suggest that expressers experience the increased metabolic clearance of TAC and low trough concentrations, which results in a high incidence of acute rejection.…”

Section: Biomarkersmentioning

confidence: 99%

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

Tajima

Suetsugu

et al. 2018

Acta Pharmacol Sin

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Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

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CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients

Abstract: Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A53. These data suggest that CYP3A422 and combined CYP3A genotypes are unlikely to provide additional information beyond CYP3A5 genotype.

Cited by 22 publications

References 42 publications

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients

Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

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