*Purpose: Variants in CYP3A4/5 genes, clinical factors and drug-drug interactions are associated with tacrolimus (TAC) clearance and dose. This results in high intra- and inter- subject variability. Moreover, high clearance and low troughs are associated with rejection. Previous models to predict TAC clearance have focused on CYP3A5 variants however CYP3A4 variants also influence metabolism. The objective of this study was to develop a TAC dosing equation accounting for genetic and nongenetic factors in kidney recipients of European ancestry.

*Methods: Adult kidney recipients receiving oral IR tacrolimus posttx from two multicenter studies were studied. Participants in the GEN03 study was used for model development (n=608) and was validated using prediction performance in the DeKAF Genomics (n=1361) study. Nonlinear mixed effect modeling was used to develop an apparent oral clearance (Cl/F) model. Three-level nested random effects were included: inter-individual variability (IIV), inter-site variability (ISV) and residual unexplained variability (RUV). CYP3A4/5 genotypes and clinical covariates were tested for their influence on Cl/F using Perl Speaks NONMEM. The bias (median prediction error, ME; median % error, MPE) and the precision (median absolute error, MAE) of population prediction (PRED) were used to assess the predictive performance.

*Results: The typical value of TAC apparent clearance (TVCL/F) was 32.2 L/hr. The estimate of IIV and ISV was 41.8% and 30.2%, respectively. Steroid, calcium channel blocker and antiviral drug use, age, diabetes, CYP3A5*1, *3 and CYP3A4*22 alleles contributed to the inter‐individual variability of TVCL/F. The bias (ME, MPE) and precision (MAE) by the model were 0.49 ng/ml, 6.5% and 3.09 ng/ml, respectively. The final model (1) and dose equation (2) are below.

(1) TVCl/F (L/hr) = 32.2 (L/hr) x [(1.81, if CYP3A5*1/*3) x (3.05, if CYP3A5*1/*1) x (0.78, if one CYP3A4*22) x (0.28, if two CYP3A4*22) x (1.06, if receiving a steroid) x (0.95, if receiving a calcium channel blocker) x (0.87, if diabetic) x (0.91, if receiving an anti-CMV viral drug) x ((AGE/52)^-0.3)] x (0.82, if TAC initiated after day 9) (2) Daily dose (mg/day) = [TVCl/F x target TAC trough concentration (ng/ml) x 24hrs]/1000

*Conclusions: The TAC model performed will and may lead to reduced time to therapeutic TAC troughs, more efficient care and better efficacy. Prospective testing of this equation is warranted.

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