In Vivo CYP3A4-Activity, CYP3A5-Genotype and Hematocrit Predict Tacrolimus Dose-Requirements and Clearance in Renal Transplant Recipients

Abstract

Introduction: Tacrolimus (Tac) is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and a high interindividual variability in pharmacokinetics. It has been hypothesized that the latter is due to interindividual differences in in vivo CYP3A4-activity and genetically determined CYP3A5 expression (CYP3A5*1 SNP). Methods: Cross-sectional study in 59 renal transplant recipients tested 3 months after transplantation investigating the relationship between in vivo CYP3A4-activity (assessed using midazolam (MDZ) as a drug probe) and CYP3A5 genotype (CYP3A5*1-allele carriers vs. CYP3A5*3/*3 homozygous patients), and Tac pharmacokinetics (assessed using dose interval concentration time profiles), taking into account other possible determinants of Tac disposition. Of note, systemic MDZ clearance (MDZ Cl) reflects hepatic CYP3A4-activity, whereas apparent oral MDZ clearance (MDZ Cl/F) reflects in vivo CYP3A4 mediated first pass metabolism and thus combined intestinal and hepatic CYP3A4-activity. Results: Baseline characteristics did not differ between CYP3A5 expressers (CYP3A5*1-allele carriers, n=10) and non-expresser (CYP3A5*3/*3 homozygous patients, n=49). Tac dose requirements (D), dose corrected AUC (AUC0-12/D) and clearance (Clss) were respectively 1.8-fold higher, 2-fold lower and 1.8-fold higher in CYP3A5 expressers. MDZ Cl and MDZ Cl/F did not differ between genotype groups. Figures 1 and 2 depict the relationship between MDZ Cl/F and Tac D (Fig 1) and Tac Clss (Fig 2) in CYP3A5 expressers (red dots) and non-expressers (blue dots), as well as the bivariate (MDZ Cl/F and CYP3A5 genotype) models predicting Tac D and Tac Clss respectively. In multivariate regression analysis MDZ Cl/F, CYP3A5 genotype and hematocrit independently predicted Tac D, Tac AUC0-12/D and Tac Clss: model R2 0.60-0.70, partial R2CYP3A5 genotype 0.31-0.33, partial R2 MDZ Cl/F 0.25-0.26 and partial R2 hematocrit 0.04-0.11 (p< 0.0001 for all).[Fig 1][Fig 2]Conclusion: In renal transplant recipients in vivo CYP3A4-activity (reflected by apparent oral midazolam clearance) and CYP3A5 genotype explain 55-60 % of interindividual variability in tacrolimus dose-requirements and clearance, while hematocrit accounts for an additional 10 %. These results demonstrate the importance of CYP3A mediated tacrolimus metabolism for explaining the clinically observed high interindividual variability in tacrolimus pharmacokinetics and provide a potential basis for a comprehensive approach in predicting tacrolimus dose requirements in individual patients.