Date: Monday, June 3, 2019
Session Time: 4:30pm-6:00pm
Presentation Time: 4:30pm-4:42pm
Location: Room 210
*Purpose: CYP3A polymorphisms are an important pharmacotherapeutic consideration due to the extensive CYP metabolism of tacrolimus (TAC) and variable expression among different races. The CPIC guideline for TAC and CYP3A5 categorizes individuals with *3, *6, and *7 alleles as poor metabolizers while there are no current guidelines to address CYP3A4*22 variances. We aim to assess the clinical differences between the loss of function alleles, CYP3A5*3, *6, *7 and CYP3A4*22 in a cohort of kidney transplant recipients (KTR) receiving standardized weight-based dosing of TAC.
*Methods: A single center retrospective longitudinal cohort study of KTRs expressing CYP3A homozygous or heterozygous loss of function alleles over a 24 month period (2013-2015) who received initial weight-based dosing of oral TAC (0.1mg/kg/day) as part of maintenance immunosuppression were analyzed for time to therapeutic TAC trough (TTT, defined as 7-11 ng/mL), percentage of undetectable TAC troughs at hospital discharge (PUT), actual TAC troughs (ATT) at hospital discharge and mg/kg therapeutic total daily dose requirements (TDD).
*Results: A total of 171 KTR were included in the study, comprising of homozygous CYP3A5*3/*3 (*3 only group, n=53) vs heterozygous CYP3A5*3/*6, *3/*7, or homozygous *6/*6 , or *7/*7 (mixed group, n=19) expressers and CYP3A4*22 (n=6) vs non-*22 expressers (n=157). Mixed group had a longer TTT (11 days vs 6.7 days, p=0.02), and a lower ATT (3.8 vs 6.3 ng/mL, p=0.006), compared to *3 only group, respectively. There was a trend toward higher PUT (16% vs 4%, p=0.11), and a higher TDD (0.11 vs 0.09 mg/kg/day, p=0.06), compared with *3 only group, respectively. There were no statistically significant differences in outcomes between CYP3A4*22 vs non-*22 with the exception of TDD (0.08 mg/kg/day vs 0.12 mg/kg/day, p=0.01). However, there were clinically important differences between *22 vs non*22 including TTT 7.7 vs 11.6 days, PUT 0% vs 22%, and ATT 6 ng/mL vs 4.1 ng/mL. All *6 or *7 expressers were African American (AA) and 5 out of 6 *22 expressers were Caucasian.
*Conclusions: We confirm that predominantly Caucasian patients who express CYP3A4*22 require the lowest amount of TAC TDD (0.08 mg/kg/day) and may have clinically significant differences in TAC outcomes, however studies with larger numbers are needed. In contradistinction to their *3 counterparts, AA patients who express *6 or *7 are slower to reach TAC goals, are often discharged from the hospital with an undetectable TAC level and require a higher initial TAC dose.
To cite this abstract in AMA style:Maldonado AQ, Irish W, Asempa TE, Gooden J, Davis ML, Haisch C, Jones H, Leeser D, Rebellato L. Not All Poor Metabolizers Are Clinically Equal: Evaluating Weight-Based Tacrolimus Outcomes in CYP3A Loss of Function Variants [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/not-all-poor-metabolizers-are-clinically-equal-evaluating-weight-based-tacrolimus-outcomes-in-cyp3a-loss-of-function-variants/. Accessed December 13, 2019.
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