Comparative performance of oral midazolam clearance and plasma 4-hydroxycholesterol to explain interindividual variability in tacrolimus clearance

AimsWe compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4-hydroxycholesterol/cholesterol (4-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. MethodsFor a cohort of 147 patients, 8h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others. ResultsMDZ Cl/F/W, 4-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r=0.262-0.505). Neither MDZ Cl/F/W nor 4-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n=29). For CYP3A5 non-expressors (n=118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R-2=0.201), haematocrit (R-2=0.139), TAC formulation (R-2=0.107) and age (R-2=0.032; total R-2=0.479). In the 4-OHC/C/W-based model, predictors were 4-OHC/C/W (R-2=0.196), haematocrit (R-2=0.059) and age (R-2=0.057; total R-2=0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4-OHC/C/W (R-2=0.167), MDZ Cl/F/W (R-2=0.045); Tac QD formulation (R-2=0.036), and haematocrit (R-2=0.032; total R-2=0.315). 4-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors. ConclusionsA MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4-OHC/C/W was superior in a model in which no genotype information was available, likely because 4-OHC/C/W was influenced by the CYP3A4*1b polymorphism.