CYP3A5 genotyping-guided dosing versus weight-based dosing in a multi-ethnic population of kidney transplant recipients

Abstract

Introduction

Tacrolimus is the cornerstone of immunosuppression after kidney transplantation (KTx) and is characterized by a narrow therapeutic index and large inter-individual variability. Pre-transplant CYP3A5 genotyping to guide tacrolimus dosing may help achieve target levels more rapidly and improve outcomes, but its impact remains unclear in our local multiethnic population where CYP3A5 expression may differ amongst ethnic groups. This pilot study aimed to investigate the impact of CYP3A5-guided tacrolimus dosing on target achievement after KTx in our multi-ethnic population.

Methods

This was a pilot single-centre study comparing CYP3A5-guided (0.20 mg/kg/day for normal and intermediate metabolizers and 0.15 mg/kg/day for poor metabolizers) with weight-based (0.10-0.20 mg/kg/day) tacrolimus dosing in living donor KTx recipients from January 2016 to June 2023. Primary outcomes were proportions of patients within target trough levels on day 3 and day 7 after tacrolimus initiation.

Results

The study included 51 patients (13 CYP3A5-guided, 38 weight-based). CYP3A5 expression differed between the Chinese and non-Chinese groups (p = .02). Initial median tacrolimus dose was higher in the CYP3A5-guided group (0.16 vs 0.12 mg/kg/day, p < .001). Proportions of patients who achieved target levels did not differ between the two groups on day 3 (46.2% vs 18.4%, p = .07) and day 7 (50.0% vs 34.2%, p = .50) after tacrolimus initiation. Median days to target trough levels were shorter in the CYP3A5-guided group (5 vs 7, p = .03). Hyperkalemia (>5.5 mmol/L) was higher in the CYP3A5-guided group (53.8% vs 21.1%, p = .04).

Conclusion

CYP3A5 expression differed amongst ethnic groups. CYP3A5-guided tacrolimus dosing may lead to faster achievement of target trough levels but may increase risk of hyperkalemia.

Keywords

Pharmacogenetics tacrolimus CYP3A kidney transplantation

Introduction

Tacrolimus remains the cornerstone of maintenance immunosuppression after kidney transplantation (KTx). However, its use is characterized by a narrow therapeutic index and large inter-individual variability.¹ Single-nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) isoenzymes 3A4 and 3A5 genes may contribute to inter-individual differences in tacrolimus pharmacokinetics. A SNP at position 6986 of the CYP3A5 gene (rs776746; 6986A>G, CYP3A5*3) results in a splicing defect that produces a non-functional CYP3A5 protein.¹ Patients expressing at least one functional allele (CYP3A5*1) therefore requires higher tacrolimus doses to achieve similar tacrolimus concentrations than non-expressers (CYP3A5*3/*3). A meta-analysis demonstrated that CYP3A5 non-expressers had dose-adjusted trough concentrations 1.8–2.5 times higher than expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and a lower risk for rejection.²

KTx recipients are commonly initiated on tacrolimus by dose per body weight (weight-based regimens). Doses are subsequently adjusted using therapeutic drug monitoring to achieve target drug levels. However, current weight-based dosing strategies have been poorly predictive of actual doses required to attain therapeutic levels and can lead to significant delay in reaching target trough concentrations and increased risk of rejection in CYP3A5 expressers.^3,4

Pre-transplantation genotyping to guide initial tacrolimus dosing has been studied but yielded conflicting results.^5–8 Min et al demonstrated that CYP3A5 expressers had lower tacrolimus levels and increased acute cellular rejection than non-expressers, with CYP3A5 expression as an independent risk factor for cellular rejection.⁹ However, in a randomized controlled trial comparing CYP3A5 genotype-guided versus standard weight-based dosing in KTx recipients, no differences were seen in patient survival, nephrotoxicity, or acute rejection even though target tacrolimus levels were achieved earlier in the genotype-based dosing group.¹⁰

CYP3A5 genotyping differs amongst ethnic groups. CYP3A5 expressers comprises approximately 18% of patients in Caucasian groups but 51% in a local multi-ethnic KTx cohort.³ The influence of these differences on the outcomes of CYP3A5 genotyping-guided tacrolimus dosing is unclear. As such, this pilot study aimed to determine the feasibility of a larger prospective clinical trial in the local context and explore the impact of CYP3A5 genotype-guided tacrolimus dosing on target drug level achievement and clinical outcomes after KTx in a multi-ethnic population.

Methods

This was a pilot prospective single-centre study comparing CYP3A5-guided tacrolimus initiation in a prospective group (CYP3A5-guided arm; January 2021 to June 2023) against weight-based tacrolimus initiation in a historical control group (weight-based arm; January 2016 to December 2020). Adults planned for living donor KTx on triple immunosuppressants comprising of tacrolimus, mycophenolate mofetil and prednisolone were recruited prospectively in the CYP3A5-guided arm, while patients in the weight-based arm were identified and recruited retrospectively from our kidney transplant database. Patients who were initiated on non-standard tacrolimus doses, had active liver disease, had gastrointestinal disorders that might interfere with absorption of oral medications, contraindications to tacrolimus and/or on concurrent medications that were known to strongly interact with tacrolimus were excluded.

Tacrolimus was initiated in the CYP3A5-guided arm at 0.15 mg/kg/day for non-expressers based on our local institution protocol and increased the dose by 1.5-2 times (as recommended by the Clinical Pharmacogenetics Implementation Consortium Guidelines) to 0.20 mg/kg/day for CYP3A5 normal and intermediate expressers.¹ Tacrolimus doses were capped at 0.20 mg/kg/day in intermediate and normal metabolizers to ensure therapeutic effectiveness while minimizing the risk of adverse effects, including hyperkalemia and drug-induced nephrotoxicity. The doses were rounded off to the nearest 0.5 mg and administered at 8a.m. and 8p.m. on an empty stomach. In the weight-based group, it was initiated at 0.10-0.20 mg/kg/day, based on the treating physician’s discretion.

All patients received induction with two doses of 500 mg methylprednisolone with either basiliximab or anti-thymocyte globulin. For maintenance immunosuppression, patients received tacrolimus, mycophenolate mofetil 1 g twice daily (or equivalent dose of enteric-coated mycophenolate acid) and prednisolone from post-operation day 2 at 20 mg once daily for the first week, followed by weekly reduction of 2 mg until 5 mg daily. Immunosuppression may be adjusted at the discretion of treating physicians. All patients received sulfamethoxazole/trimethoprim or alternatives for Pneumocystis jirovecii prophylaxis, cytomegalovirus (CMV) prophylaxis depending on donor and recipient CMV serostatus and choice of induction agents, and nystatin for antifungal prophylaxis.

The primary endpoint was the proportion of patients who attained target tacrolimus level on day 3 and 7 after tacrolimus initiation. Tacrolimus trough levels were measured as the whole blood concentrations 12 h ± 15 min after the previous dose taken the night before at 8p.m. using liquid chromatography and tandem mass spectrometry (LC-MS/MS) and performed daily after transplantation until the patient is discharged. For the CYP3A5-guided arm, the pre-specified tacrolimus target trough was 10–15 ng/mL in the first 1 week after transplantation and subsequently adjusted based on the local transplant immunosuppression protocol. In the weight-based group, tacrolimus trough targets were 8-12 ng/mL for patients of low to moderate immunological risk and 10-15 ng/mL for those of high immunological risk based on the local transplant centre protocol and could be modified based on the treating physician’s discretion. All patients were genotyped regardless of allocation. The initiation dose for the CYP3A5-guided arm was calculated based on the genotype results by a pharmacist in the study team and recommended to the treating physicians, while the genotype results were not made known to the treating physicians. Patients in the weight-based group was genotyped retrospectively and the results were not known at the time of tacrolimus initiation. CYP3A5 genotyping was performed in an accredited external molecular laboratory using an in-house Taqman SNP genotyping assay on real-time PCR. The lab-developed assay is designed to test for CYP3A5*3 (NM_000777.4:c.219-237A>G) single nucleotide polymorphisms in genomic DNA.

All patients were followed for at least 3 months after transplantation, or until death or graft loss. Adverse events including infections (e.g. CMV and BK virus infection, infections requiring hospitalizations), post-transplant diabetes mellitus, neurological events, transaminitis and acute tacrolimus nephrotoxicity (defined as ≥15% increase in serum creatinine with return to baseline after tacrolimus dose reduction and excluding other causes of graft dysfunction) were recorded.

Categorical variables were reported as frequency and percentages while continuous variables were expressed as medians with interquartile ranges (IQRs). Differences between categorical and continuous variables were assessed using the chi-square test and the Mann-Whitney U-test, respectively. All data was analyzed using Stata/BE version 17.0 (StatCorp LCC, USA). A p-value <.05 was considered statistically significant.

The study abided by the Declaration of Helsinki, the Istanbul Declaration regarding donor source and was approved by the central institutional review board (CIRB number 2019/2599). Written informed consent was obtained from all patients.

Results

Fifty-one patients (13 CYP3A5-guided, 38 weight-based) were included in this study. Baseline demographic characteristics of the two groups were similar (Table 1). Most of the study population was Chinese (78.4%) and the most common primary kidney disease was glomerulonephritis (64.7%). CYP3A5 poor metabolizers (CYP3A5*3/*3) made up majority of the study population (51.0%) followed by intermediate metabolizers (CYP3A5*1/*3) at 45.1% and normal metabolizers (CYP3A5*1/*1) at 3.9%. There was no difference in distribution of CYP3A5 genotypes between the two groups. The proportion of poor, intermediate, and normal metabolizers (Table 2) were 47.5%, 50.0% and 2.5% in the Chinese and 63.6%, 27.3% and 9.1% in the non-Chinese respectively (p = .02). Initial tacrolimus dose was higher in CYP3A5-guided group (0.16 vs 0.12 mg/kg/day, p < .001).

Table 1.

Baseline demographics.

	Weight-based arm (n = 38)	CYP3A5-guided arm (n = 13)	p Value
Age, years (IQR)	48 (40-57)	43 (34-59)	0.76
Male, n (%)	22 (57.9%)	8 (61.5%)	1.00
Ethnicity, n (%)			0.60
Chinese	30 (78.9%)	10 (76.9%)
Malay	4 (10.5%)	2 (15.4%)
Indian	1 (2.6%)	1 (7.7%)
Others	3 (7.9%)	0 (0%)
Cause of ESKD, n (%)			0.93
Diabetes mellitus	7 (18.4%)	2 (15.4%)
Glomerulonephritis	24 (63.2%)	9 (69.2%)
Others	7 (18.4%)	2 (15.4%)
Immunological risk, n (%)			0.13
Standard risk (ABOc, DSA neg)	19 (50.0%)	5 (38.5%)
Intermediate risk (ABOc, DSA pos)	12 (31.6%)	2 (15.4%)
High risk (ABOi and/or XM pos)	7 (18.4%)	6 (46.2%)
CYP3A5 phenotype, n (%)			0.66
Poor metabolizer	19 (50.0%)	7 (53.8%)
Intermediate metabolizer	18 (47.4%)	5 (38.5%)
Normal metabolizer	1 (2.6%)	1 (7.7%)
Weight, kg (IQR)	68.3 (54.1-75.2)	69.7 (61.2-80.7)	0.41
Body Mass index, kg/m² (IQR)	24.3 (20.9-28.1)	24.4 (23.7-27.5)	0.65
Initial tacrolimus dose, mg/kg/day (IQR)	0.12 (0.10-0.15)	0.16 (0.15-0.20)	<0.001

ABOc, ABO blood group compatible; ABOi, ABO blood group incompatible; DSA neg, donor-specific antibodies negative; DSA pos, donor-specific antibodies positive; ESKD, End stage kidney disease; IQR, interquartile range; XM pos, cross match positive.

Table 2.

Distribution of CYP3A5 phenotype amongst ethnic groups.

CYP3A5 phenotype, n (%)	Chinese (n = 40)	Non-Chinese (n = 11)
Poor metabolizer	19 (47.5)	7 (63.6)
Intermediate metabolizer	20 (50.0)	3 (27.3)
Normal metabolizer	1 (2.5)	1 (9.1)

The proportions of patients who achieved desired trough levels on day 3 (46.2% vs 18.4%, p = .07) and day 7 (50.0% vs 34.2%, p = .50) after tacrolimus initiation did not differ between the CYP3A5-guided and weight-based arms (Table 3). Dose of tacrolimus (0.16 vs 0.11 mg/day/kg, p < .001) and tacrolimus troughs (12.9 vs 9.7 ng/mL, p = .046) achieved at day 3 were significantly higher in the CYP3A5-guided group compared with the weight-based group but did not differ at day 7. The median days to achieve desired tacrolimus trough was shorter in the CYP3A5-guided arm (5 vs 7, p = .03). The number of dose changes in the first 7 days after tacrolimus, percentage change between the initiation and discharge dose of tacrolimus and proportion of tacrolimus trough readings that were within the desired range did not differ between the two arms. There was no significant difference between the concentration-to-dose per body weight ratio between the poor metabolizers and intermediate/ normal metabolizers (Table S1).

Table 3.

Outcomes and adverse events.

	Weight-based arm (n = 44)	CYP3A5-guided arm (n = 19)	p value
Day 3
Tacrolimus dose, mg/kg/day (IQR)	0.11 (0.09-0.14)	0.16 (0.15-0.19)	<0.001
Tacrolimus trough, ng/mL (IQR)	9.7 (5.5-11.8)	12.9 (9.4-14.0)	0.046
Achieved tacrolimus trough, n (%)	7 (18.4%)	6 (46.2%)	0.07
Day 7
Tacrolimus dose, mg/kg/day (IQR)	0.12 (0.09-0.16)	0.18 (0.12-0.24)	0.02
Tacrolimus trough, ng/mL (IQR)	9.8 (7.9-11.6)	10.3 (8.6-11.4)	0.50
Achieved tacrolimus trough, n (%)	13 (34.2%)	6 (50.0%)	0.50
Other outcomes
Day achieved tacrolimus target, (IQR)	7 (4-9)	5 (3-5)	0.03
Number of dose adjustments in first week after initiation, n (IQR)	3 (2-4)	3 (2-5)	0.25
Percentage change from initial and discharge tacrolimus dose, % (IQR)	50 (0-90)	20 (0-50)	0.10
Proportion of readings within tacrolimus target in first week after initiation, n (%)	20 (0-36.5)	25 (20-60)	0.09
Adverse events
Transaminitis	7 (18.4%)	3 (23.1%)	0.70
Hyperkalaemia (K >5.5 mmol/L)	8 (21.1%)	7 (53.8%)	0.04
Infection requiring hospitalization	10 (26.3%)	7 (53.8%)	0.09
CMV infection	0 (0%)	1 (7.7%)	0.26
BK Virus infection	5 (13.2%)	0 (0%)	0.31
PTDM	4 (13.8%)	4 (40.0%)	0.17
Biopsy-proven rejection	2 (5.3%)	3 (23.1%)	0.10

CMV, cytomegaIovirus; IQR, interquartile range; PTDM, post-transplant diabetes mellitus.

Incidence of hyperkalemia (K >5.5 mmol/L) within the first 3 weeks after tacrolimus initiation was higher in the CYP3A5-guided arm (53.8% vs 21.1%, p = .04). All cases of hyperkalemia resolved with short courses of pharmacological therapy e.g. cation exchanger resins and/or insulin with glucose. There were no significant differences between the two arms for other adverse events such as transaminitis, infections requiring hospitalizations, post-transplant diabetes mellitus and biopsy-proven rejection (Table 3).

Discussion

The proportions of patients achieving target tacrolimus trough levels at day 3 and 7 after initiation were not different between the CYP3A5-guided and weight-based groups in this study. However, the study showed that CYP3A5-guided dosing may allow patients to achieve tacrolimus target levels more rapidly. While tacrolimus doses and trough levels achieved at day 3 after initiation differed between the two groups, differences mostly converged by day 7. We were able to successfully implement our study protocol but recruitment was hampered by the COVID-19 pandemic and a subsequent change in our centre’s maintenance immunosuppression protocol, demonstrating the difficulty in recruiting adequate subjects in a single-centre study in the local context.

A previous randomized-controlled study similarly showed no difference in the proportion of patients achieving target tacrolimus levels at day 3 after initiation between the standard-dose and CYP3A5 genotype-guided groups.⁷ In contrast, in a study by Thervet et al, more patients in the CYP3A5-guided group attained target drug levels at day 3 after initiation and achieved target levels more rapidly with fewer dose adjustments.¹⁰ A key difference in this study was that patients were only initiated on tacrolimus 7 days post-transplantation. These inconsistencies may be explained by higher inter-patient variability in tacrolimus metabolism in initial days following transplantation compared to the variability observed after a week. Factors such as postoperative changes in gastrointestinal motility and glucocorticoid doses may lead to higher inter-patient tacrolimus variabilities and dilute the impact of CYP3A5-guided dosing.^11,12 Tacrolimus levels may also be affected by multiple other factors such as changes in volume of distribution due to changes in fluid status post-transplant, metabolism by alternate cytochrome pathways and perioperative alterations in liver function which could have masked the potential benefit of CYP3A5-guided dosing.^13,14

Similar to previous randomized controlled trials and meta-analyses, our study did not demonstrate improved clinical outcomes with CYP3A5-guided tacrolimus dosing.^6,7,10,15,16 This is likely contributed by the short follow-up duration and small sample size. Moreover, potential benefits of achieving target blood tacrolimus concentrations earlier may have been diminished by other factors such as potent immunosuppression and anti-microbial prophylaxis used during transplantation. In this study, there was no increased risk of adverse events except for hyperkalaemia. Previous studies did not report any difference in adverse events between the two different dosing strategies.^7,10 The higher incidence of hyperkalemia in our study could be related to higher tacrolimus exposure in expressors of the CYP3A5-guided group from genotype-based dosing.^17,18 Nonetheless, it remains crucial to monitor for tacrolimus-associated adverse effects regardless of dosing strategy.

Distribution of CYP3A5 genotypes is different amongst ethnic groups and may influence tacrolimus dosing. Similar to a previous local study, nearly half of our cohort were CYP3A5 expressors, compared to previous cohorts with predominantly Caucasian populations, where only 10% were CYP3A5 expressors.^3,4 As such, pre-transplant CYP3A5 testing may be more likely to modify the initial tacrolimus dosage than Caucasian cohorts. We also showed that the non-Chinese had a higher proportion of normal metabolizers. Therefore, pre-transplant CYP3A5 genotyping may be more likely to benefit certain ethnic groups if it has a higher likelihood of optimizing tacrolimus dosing.

The aim of this pilot study was to determine the feasibility of a larger prospective clinical trial in the local context and it was not designed to detect differences in the primary outcomes. Moreover, initial tacrolimus dosing and target trough levels were not standardized in the retrospective weight-based arm and could be modified based on the treating physician’s discretion. Therefore, the mean starting tacrolimus dose in the weight-based group was lower than 0.15 mg/kg/day and significantly lower than that of the CYP3A5-guided group. As such, comparison between the two groups was challenging and differences between the two groups could be contributed by the overall higher initiation dose and a closer adherence to the protocol in the CYP3A5-guided group. The study design by Thervet et al where normal metabolizers received a starting tacrolimus dose of 0.3 mg/kg/day and poor metabolizers at 0.15 mg/kg/day, while patients in the control group received 0.2 mg/kg/day may overcome some of these limitations. A randomized controlled trial could be considered in the future. In addition, although a gene–dose effect has been observed for CYP3A5 genotype and tacrolimus dose requirement, CYP3A5*1 carriers and CYP3A5*1 homozygotes received the same tacrolimus dose in our study, similar to that of previous studies.^7,10 However, to the best of our knowledge, this is the first pilot study to investigate the impact of CYP3A5-guided tacrolimus initiation in a multiethnic Southeast Asian cohort. The findings of this study could help plan for larger studies in the future to clarify the impact of pre-transplant CYP3A5 genotyping. Furthermore, development of a population pharmacokinetic model that incorporates patient’s genetic information together with other clinical and demographic factors that influence tacrolimus pharmacokinetics should be considered to predict the patient’s tacrolimus dose requirement more accurately.^16,19,20 To improve the understanding of tacrolimus dosing particularly in the local population, further subgroup analyses based on CYP3A5 genotype would be beneficial. However, the current sample size limits the power of such analyses.

Conclusion

In conclusion, CYP3A5 genotype expression may differ amongst our local ethnic groups. CYP3A5 genotype-guided tacrolimus dosing may help patients achieve target trough levels more rapidly but may increase the risk of hyperkalemia.

Supplemental Material

Supplemental Material - CYP3A5 genotyping-guided dosing versus weight-based dosing in a multi-ethnic population of kidney transplant recipients

Supplemental Material for CYP3A5 genotyping-guided dosing versus weight-based dosing in a multi-ethnic population of kidney transplant recipients by Rou Wei Lim, Quan Yao Ho, Yan Ting Yeo, Ian Tatt Liew, Carolyn Shan-Yeu Tien, Sobhana Thangaraju, Puay Hoon Lee, Terence Kee in Proceedings of Singapore Healthcare

Footnotes

Acknowledgments

We would like to extend our appreciation to all the study participants who made this study possible.

Author contributions

All authors were involved in protocol development, patient recruitment, data collection and analysis, drafted the manuscript, and critically revised the manuscript for important intellectual content.

Declaration of conflicting interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Lee Foundation Grant (SDTC/LFG/2021/005).

Ethical statement

Informed consent

Written informed consent was obtained from the patients for their anonymized information to be published in this article.

ORCID iDs

Rou Wei Lim

Yan Ting Yeo

Ian Tatt Liew

Carolyn Shan-Yeu Tien

Terence Kee

Data Availability Statement

All data generated or analysed during the present study are available from the corresponding author on reasonable request. *

Supplemental Material

Supplemental material for this article is available online.

Appendix

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