Document Type
Article
Publication Date
2-2022
Abstract
Study Objective: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients.
Design and Setting: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC0–12), AUC0–4, 12-h troughs (C12 h), maximum concentrations (Cmax), oral clearance (Cl), with dose-normalized AUC0–12, troughs, and Cmax with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms.
Patients: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated.
Measurements and Main Results: Black recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was <100 >ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p < 0.001), and Cl (p < 0.001).
Conclusions: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h.
Recommended Citation
Tornatore, K.M., Meaney, C.J., Attwood, K., Brazeau, D.A., Wilding, G.E., Consiglio, J.D., Gundroo, A., Chang, S.S., Gray, V., Cooper, L.M. and Venuto, R.C., 2022. Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 42(2), pp.94-105.
Comments
The copy of record is available from the publisher at https://doi.org/10.1002/phar.2656.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Copyright © 2022 The Authors.