Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant

Hannachi, Ibtissem; Fredj, Nadia Ben; Chadli, Zohra; Fadhel, Najah Ben; Romdhane, Haifa Ben; Touitou, Yvan; Boughattas, Naceur A.; Chaabane, Amel; Aouam, Karim

doi:10.1016/j.taap.2020.115000

Cited by 8 publications

(10 citation statements)

References 43 publications

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“…17 Although BSA had a significant effect on the CL of tacrolimus, it was not included in previous Tunisian PK studies. [52][53][54] Compared with previous investigations on Tunisian patients, this study consisted of a relatively larger cohort, tested a diverse range of potential covariates, and used a popPK approach for model development. [52][53][54] The number of patients included in the study by Gaïes et al 52 was small (n = 20) and did not investigate the effect of CYP3A5*3; only bodyweight influenced the apparent central volume of distribution.…”

Section: Discussionmentioning

confidence: 99%

“…[52][53][54] Compared with previous investigations on Tunisian patients, this study consisted of a relatively larger cohort, tested a diverse range of potential covariates, and used a popPK approach for model development. [52][53][54] The number of patients included in the study by Gaïes et al 52 was small (n = 20) and did not investigate the effect of CYP3A5*3; only bodyweight influenced the apparent central volume of distribution. Two separate studies have been conducted on 53 patients/409 C0 53 and 50 patients/309 C0 51 , compared with 196 patients/1901 C0 for our study's cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Two separate studies have been conducted on 53 patients/409 C0 53 and 50 patients/309 C0 51 , compared with 196 patients/1901 C0 for our study's cohort. These investigative works only tested the effect of 7 covariates on tacrolimus PK using a nonparametric approach, [52][53][54] whereas here, we examined 20 covariates using NONMEM. Furthermore, these 2 studies did not find any effect of CYP3A5*3 on tacrolimus CL.…”

Section: Discussionmentioning

confidence: 99%

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A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation

Abderahmene,

Francke,

Andrews

et al. 2023

Therapeutic Drug Monitoring

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Background: Tacrolimus is the most frequently used immunosuppressive drug for preventing renal rejection. However, its use is hampered by its narrow therapeutic index and large intra and interpatient variability in pharmacokinetics. The objective of this study was to externally validate a tacrolimus population pharmacokinetic model developed for the Dutch population and adjust the model for the Tunisian population for use in predicting the starting dose requirement after kidney transplantation. Methods: Data on tacrolimus exposure were obtained from kidney transplant recipients (KTRs) during the first 3 months post-transplantation. External validation of the Dutch model and its adjustment for the Tunisian population was performed using nonlinear mixed-effects modeling. Results: In total, 1901 whole-blood predose tacrolimus concentrations from 196 adult KTRs were analyzed. According to a visual predictive check, the Dutch model underestimated the starting dose for the Tunisian adult population. The effects of age, together with the CYP3A5*3 and CYP3A4*22 genotypes on tacrolimus clearance were significantly different in the Tunisian population than in the Dutch population. Based on a bodyweight-based dosing, only 21.9% of tacrolimus concentrations were within the target range, whereas this was estimated to be 54.0% with the newly developed model-based dosing. After adjustment, the model was successfully validated internally in a Tunisian population. Conclusions: A starting-dose population pharmacokinetic model of tacrolimus for Tunisian KTRs was developed based on a previously published Dutch model. Using this starting dose could potentially increase the percentage of patients achieving target tacrolimus concentrations after the initial starting dose.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation

Abderahmene,

Francke,

Andrews

et al. 2023

Therapeutic Drug Monitoring

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“…A previous study suggested that CYP3A4*22 was significantly related to increased tacrolimus concentrations in 1560 European-American kidney transplant recipients. 21 However, the CYP3A4*22 and CYP3A4*1B SNPs have frequencies of less than 1% Asian populations. Thus, in our study, no mutation was observed in the CYP3A4*1B allele, and only one patient carried the minor allele of CYP3A4*22.…”

Section: Discussionmentioning

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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“…Despite these findings, the interindividual variability in Tac pharmacokinetics has not been adequately explained [12,13], as the pharmacokinetics vary among CYP3A5 expressers and non-expressers. Therefore, polymorphisms in other candidate genes have been investigated to explain the interindividual variability in Tac pharmacokinetics [14].…”

Section: Introductionmentioning

confidence: 99%

The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients

Furuse

Hosomi

et al. 2021

PLoS ONE

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Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

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Effect of CYP3A422 and CYP3A41B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant

Cited by 8 publications

References 43 publications

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation

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

The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients

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