期刊
PHARMACOTHERAPY
卷 42, 期 2, 页码 94-105出版社
WILEY
DOI: 10.1002/phar.2656
关键词
immunosuppression; race; renal transplantation; sex; tacrolimus pharmacokinetics
资金
- NIDDK ARRA [R21: DK077325-01A1]
- Investigator-Initiated Research Grants (KMT-PI) from Astellas Pharma Global Development, Inc.
This study found that race and sex differences in stable kidney transplant recipients can affect tacrolimus pharmacokinetics and adverse effects, with more cumulative, neurologic, and aesthetic adverse effects noted among female patients.
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 (AUC(0-12)), AUC(0-4), 12-h troughs (C (12 h)), maximum concentrations (C (max)), oral clearance (Cl), with dose-normalized AUC(0-12), troughs, and C (max) 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 AUC(0-12) (Race: p = 0.005), lower AUC* (Race: p p = 0.068), and higher Cl (Race: p p = 0.066). Greater cumulative (Sex: p p = 0.014), neurologic (Sex: p = 0.021; Race x 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 AUC(0-12) was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC(0-12) 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); AUC(0-12 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 AUC(0-12 h).
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