Impact of CYP3A5 phenotype on tacrolimus time in therapeutic range and clinical outcomes in pediatric renal and heart transplant recipients

Abstract

Study Objective This study investigated the effect of CYP3A5 phenotype on time in therapeutic range (TTR) of tacrolimus post‐transplant in pediatric patients. Design and Data Source This retrospective study assessed medical records of pediatric kidney and heart recipients with available CYP3A5 genotype for tacrolimus dosing, troughs, and the clinical events (biopsy‐proven acute rejection [BPAR] and de novo donor‐specific antibodies [dnDSA]). Measurements and Main Results The primary outcome, mean TTR in the first 90 days post‐transplant, was 9.0% (95% CI: −16.1, −1.9) lower in CYP3A5 expressers (p = 0.014) when adjusting for time to therapeutic concentration and organ type. There was no difference between CYP3A5 phenotypes in time to the first clinical event using TTR during the first 90 days. When applying TTR over the first year, there was a significant difference in event‐free survival (EFS) which was 50.0% for CYP3A5 expressers/TTR < 35%, 45.5% for expressers/TTR ≥ 35%, 38.1% for nonexpressers/TTR < 35%, and 72.9% for nonexpressers/TTR ≥ 35% (log‐rank p = 0.03). A post hoc analysis of EFS identified CYP3A5 expressers had lower EFS compared to nonexpressers in patients with TTR ≥ 35% (p = 0.04) but no difference among patients with TTR < 35% (p = 0.6). Conclusions The relationship between TTR and CYP3A5 phenotype suggests that achieving a TTR ≥ 35% during the first year may be a modifiable factor to attenuate the risk of BPAR and dnDSA.

Lower tacrolimus time in therapeutic range is associated with inferior outcomes in adult liver transplant recipients

“…Additionally, pharmacogenetics, food intake and gastrointestinal disorders are all potential factors that have been considered but have not been thoroughly evaluated 12 . In paediatric renal and heart transplantation patients, recent studies have demonstrated that TTR in the early posttransplant period is associated with the CYP3A5 phenotype 38 . Given the Tac TTR may be related to some factors, different strategies have been proposed to increase Tac TTR.…”

“…Previous studies have shown that fewer dose changes, better adherence compliance and avoiding administration of CYP3A4‐interfering medications can help increase TTR levels 14,39 . Interventions to reduce non‐adherence, including the timing and dosing, can also improve the TTR of Tac, resulting in superior outcomes 14,38 . In addition, patient‐based interventions can be used to reduce IPV, including increasing the frequency of follow‐up and education actions 40 …”

“…12 In paediatric renal and heart transplantation patients, recent studies have demonstrated that TTR in the early posttransplant period is associated with the CYP3A5 phenotype. 38 Given the Tac TTR may be related to some factors, different strategies have been proposed to increase Tac TTR. Previous studies have shown that fewer dose changes, better adherence compliance and avoiding administration of CYP3A4-interfering medications can help increase TTR levels.…”

“…14,39 Interventions to reduce non-adherence, including the timing and dosing, can also improve the TTR of Tac, resulting in superior outcomes. 14,38 In addition, patient-based interventions can be used to reduce IPV, including increasing the frequency of follow-up and education actions. 40 Our study has several limitations.…”

Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients

“…Additional information on posttransplant immunosuppression is published elsewhere. 3 Briefly, both kidney and heart transplant recipients were administered immediate-release tacrolimus according to a weight-based dosing protocol (kidney: 0.1 mg/kg per dose twice a day or thrice a day, heart: 0.05 mg/kg per dose twice a day) combined with mycophenolate or azathioprine. Kidney transplant recipients received either standard or steroid-avoidant immunosuppressive treatment, whereas all heart transplant recipients received standard steroid-based immunosuppressive treatment.…”