The local ethnic population of kidney transplant recipients in Singapore has a diverse CYP3A5 genotype expression, according to a study. A CYP3A5-guided dosing of tacrolimus may help these patients achieve target trough levels at a faster rate, but it can also put them at greater risk of hyperkalaemia.
In this pilot single-centre study, a group of researchers compared 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 kidney transplant recipients from January 2016 to June 2023.
The proportion of patients who achieved target trough levels on days 3 and 7 after initiating tacrolimus was the primary outcome. [Proc Singap Healthc 2025;doi:10.1177/20101058251365300]
Fifty-one patients were included in the analysis of whom 15 received CYP3A5-guided dosing and 38 weight-based dosing. CYP3A5 expression differed between the Chinese and non-Chinese patient population (p=0.02).
Patients in the CYP3A5-guided group had a higher initial median tacrolimus dose than those in the weight-guided group (0.16 vs 0.12 mg/kg/day; p<0.001). The primary outcome did not differ between the two treatment groups on day 3 (46.2 percent vs 18.4 percent; p=0.07) and day 7 (50.0 percent vs 34.2 percent; p=0.50) following tacrolimus initiation.
Furthermore, the CYP3A5-guided group had shorter median days to target trough levels (5 vs 7 days; p=0.03) but had a significantly increased risk of hyperkalaemia (>5.5 mmol/L; 53.8 percent vs 21.1 percent; p=0.04).
“Similar to previous randomized controlled trials and meta-analyses, our study did not demonstrate improved clinical outcomes with CYP3A5-guided tacrolimus dosing,” the researchers said. [Am J Transplant 2016;16:2670-2675; Am J Transplant 2016;16:2670-2675; Clin Pharmacol Ther 2010;87:721-726; Pharmacogenet Genomics 2012;22:642-645; Clin Pharmacokinet 2021;60:877-885]
Such finding is potentially driven by the short follow-up duration and small sample size. Other factors such as potent immunosuppression and antimicrobial prophylaxis used during transplantation may have lessened the potential benefits of achieving target blood tacrolimus concentrations as well.
Adverse events
The current study did not find an increased risk of adverse events except for hyperkalaemia. In earlier studies, there was also no difference noted in adverse events between the two dosing strategies. [Clin Pharmacokinet 2021;60:877-885; Clin Pharmacokinet 2021;60:877-885]
“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,” the researchers said. [Clin Pharmacokinet 2021;60:877-885; Indian J Nephrol 2022;32:240-246]
“Nonetheless, it remains crucial to monitor for tacrolimus-associated adverse effects regardless of dosing strategy,” they added.
Ethnic groups
The various distribution of CYP3A5 genotypes among ethnic groups 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 percent were CYP3A5 expressors,” the researchers said. [Transplant Proc 2008;40:1690-1695; Am J Transplant 2004;4:914-919]
“As such, pretransplant CYP3A5 testing may be more likely to modify the initial tacrolimus dosage than Caucasian cohorts,” they added.
Moreover, the non-Chinese ethnic group showed a higher proportion of normal metabolizers.
“Therefore, pretransplant CYP3A5 genotyping may be more likely to benefit certain ethnic groups if it has a higher likelihood of optimizing tacrolimus dosing,” according to the researchers.