Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives

Degraeve, Alexandra L.; Moudio, Serge; Haufroid, Vincent; Eddour, Djamila Chaïb; Mourad, Michel; Bindels, Laure B.; Elens, Laure

doi:10.1080/17425255.2020.1803277

Cited by 26 publications

(28 citation statements)

References 198 publications

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“…CYP3A5 is the predominant tacrolimus metabolic pathway, and previous studies have indicated that this enzyme to be the most significant source of tacrolimus pharmacokinetic variability 18,19 . In addition, CYP3A4*22 (rs35599367), CYP3A4*1B (rs2740574), ABCB1 3435C>T (rs1128503, rs2032582 and rs1045642), ABCC2 (rs717620, rs2273697 and rs3740066), POR*28 (rs1057868) and PXR (rs6785049) were investigated, which these SNPs may help provide information concerning additional tacrolimus concentration variability beyond the effects of CYP3A5 12,20,21 . The CYP3A4*22 and CYP3A4*1B alleles were suggested to be correlated with the reduced expression of the CYP3A4 enzyme and alteration of tacrolimus pharmacokinetics 22,23 .…”

Section: Discussionmentioning

confidence: 99%

“…Through in vivo and in vitro pharmacokinetic studies demonstrated that WZC inhibited P‐gp‐mediated efflux and CYP3A‐mediated metabolism of tacrolimus and then increased tacrolimus oral bioavailability 10,11 . Furthermore, several pharmacogenetic studies have focussed on investigating the effects of ABCB1, ABCC2, POR and PXR genes on tacrolimus metabolism 12,13 . Studies have shown that the aforementioned genes are associated with alterations in the pharmacokinetics of tacrolimus by affecting the CYP3A or P‐gp mediated metabolism process 14,15 .…”

Section: What Is Known and Objectivementioning

confidence: 99%

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Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Cheng

Wang

et al. 2021

J Clin Pharm Ther

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What is known and objective Tacrolimus (FK506), an effective and potent calcineurin inhibitor, is the cornerstone of immunosuppression after kidney transplantation. Wuzhi capsule (WZC), a prescribed ethanol extract of Nan‐Wuweizi (Schisandra sphenanthera), is widely prescribed for kidney transplant recipients for the maintenance of tacrolimus concentration in clinical settings. Previous studies have demonstrated that WZC can increase the blood concentration of tacrolimus. However, it remains controversial whether to use WZC can be used to increase tacrolimus concentration in clinical practice. Our study aimed to evaluate the efficacy and safety of WZC combined with tacrolimus in the treatment of kidney transplant recipients. Methods One hundred and ninety four Chinese kidney transplant recipients were included in this retrospective study. The recipients were divided into two groups (non‐WZC group and WZC group). We investigated the effects of WZC on tacrolimus in terms of tacrolimus metabolism, laboratory tests, pharmacogenomics, renal function and adverse reactions. Results and Discussion The concentration/dose (C0/D) of tacrolimus was significantly higher in the WZC group than the non‐WZC group. The laboratory findings of blood routine tests, liver and kidney function were not significantly different between the two groups. The CYP3A5 genotype showed clearly associated with tacrolimus C0/D, whereas no significant difference was observed in patients with CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. The improvement of C0/D by administration of WZC was significant in CYP3A5 expressers compared to non‐expressers. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached the target tacrolimus concentration than the non‐WZC group. No significant differences in renal function and adverse reactions were observed between the groups. What is new and conclusion Wuzhi capsule can increase tacrolimus concentration without negative effects on renal function and adverse reactions, especially in CYP3A5 expressers. Efficient and economical synergistic effects can be achieved by the combined administration of WZC in kidney transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Section: What Is Known and Objectivementioning

confidence: 99%

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Cheng

Wang

et al. 2021

J Clin Pharm Ther

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“…We acknowledge that our study had several limitations. Its retrospective design did not allow us to collect data on the co-medications of patients nor did it allow us to genotype the CYP3A5 data although the drugs that inhibit cytochrome 3A4/3A5 or cytochrome P4503A/5 genetic polymorphisms highly contributed to tacrolimus Cmin variability [15]. In addition, few data were available to describe the adjustments of the dose of tacrolimus that was prescribed by the clinicians after an episode of tacrolimus overdosage.…”

Section: Discussionmentioning

confidence: 99%

“…Individual demographic characteristics, such as age, gender, ethnicity, or poor compliance are known to influence tacrolimus Cmin [11], as are genetic polymorphisms of CYP3A4/5 [12], co-medication with a 3A4/5 inducer or inhibitor [13], or liver dysfunction [14] due to the extensive cytochrome P450 3A4/5-dependent pathway of tacrolimus metabolism [15].…”

Section: Introductionmentioning

confidence: 99%

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

et al. 2021

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Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th–90th percentiles): 27 mg/L (3–149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3–95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration.

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“…In recent years, genetic factors have been considered to play an important role in the interindividual and interethnic variability of tacrolimus. 3 Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5) and CYP3A4 enzymes. 4 , 5 Therefore, allelic variation of CYP3A5 and CYP3A4 genes can explain most of the tacrolimus PK variability.…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients

Cheng¹,

Li²,

Wang³

et al. 2021

PGPM

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Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives

Cited by 26 publications

References 198 publications

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients

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