A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype‐Based With Body‐Weight‐Based Tacrolimus Dosing After Living Donor Kidney Transplantation

Abstract

Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weightbased or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

“…The second trial, however, found no such advantage of CYP3A5-based dosing with 37.4% of patients receiving the standard bodyweight-based dose being within the Tac concentration range compared with 35.6% of the genotype-based group at first steady state. There was also no difference in the time to reach the target Tac concentration or the number of dose adjustments [98]. The explanation for this finding was that in the genotypebased arm, CYP3A5 non-expressers tended to have subtherapeutic concentrations more often after receiving the reduced starting dose.…”

“…In both trials, kidney transplant recipients were randomized to either receive the standard, bodyweight-based Tac dose (0.2 mg/kg/day) or to receive a dose customized to the CYP3A5 status of the patient (expressers 0.3 mg/kg/day and non-expressers 0.15 mg/kg/day) [98,99]. In the first study, genotype-based dosing resulted in significantly more patients being within the target Tac concentration range, 3 days after starting Tac (43.2%), compared with patients receiving the standard, bodyweight-based dose (29.1%).…”

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…[28] In a second RCT, 240 renal transplant recipients were randomized to receive a standard, bodyweight-based Tac starting dose (0.1 mg/kg twice daily) or a CYP3A5 genotype-based starting dose (0.075 or 0.15 mg/kg twice daily for CYP3A5 non-expressers and expressers, respectively). [29] Unlike the Tactique study, this trial only included recipients of a living kidney donor (who were genotyped for CYP3A5 during the workup for transplantation) and Tac was started on the day of transplantation rather than at day 7 post-transplant. All patients received basiliximab induction therapy and a standard MMF starting dose of 2 g/day followed by TDM.…”

Predictive Modeling of Tacrolimus Dose Requirements: “All That Is Gold Does Not Glitter”

“…The majority of white patients (80% CYP3A5*3/*3) are initially overexposed with a standard tacrolimus loading dose (0.2 mg/ kg) (3)(4)(5). Because all tacrolimus concentrations (whether in the fixed-or adapted-dose group) are considered to be in steady state on day 10 (no dose changes allowed until then), the differences in PSL1 model performance in these subgroups (supplementary table 3 in Damon et al) cannot be explained by different dosing strategies, as the authors suggest (1).…”