Guiding the starting dose of the once-daily formulation of tacrolimus in " de novo" adult renal transplant patients: a population approach

Abstract

Aims: The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.

Methods: A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5.

Results: A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger.

Conclusion: The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60 years or younger would be highest, while CYP3A5*/1 non-carriers older than 60 years would require the lowest doses.

Keywords: CYP3A4; CYP3A5; ER-Tac; age; de novo-kidney transplant patients; hematocrit; population pharmacokinetics.

FIGURE 1

Tacrolimus blood concentration–time profiles after oral administration of the once-daily extended-release formulation in de novo kidney transplant patients. Filled blue circles represent the observed concentration. The mean trend of the data is shown by the red solid line that represents a smooth regression using the LOESS non-parametric method. The blue band is the 95% confidence interval of the mean trend.

FIGURE 2

Prediction-corrected VPC results. Prediction-corrected visual predictive check of tacrolimus blood concentration (expressed as ng/mL) vs. time (time after the last dose given in h) profiles. Open circles represent the prediction-corrected observed concentration. In general, median (solid red line), 95th, and fifth percentiles (dashed red lines) of the observations, as well as the 90% confidence intervals (CI) for the median, 5th, and 95th percentiles of the simulated profiles (covered by the light blue areas) are superimposed in each graph. The fifth, 50th, and 95th percentile lines of the observations fell inside the area of the corresponding 90% CI.

FIGURE 3

Box plots of C_trough simulated values on day 5 from the start of the once-daily doses of 5, 5.5, 6, 6.5, 7, and 7.5 mg of the ER-Tac formulation (corresponding to 0.07, 0.08, 0.09, 0.093, 0.100, and 0.110 mg/kg for a typical patient of 70-kg bodyweight; i.e., the mean value of the target population). Concentrations of patients with hematocrit levels ranging from 0.22 to 0.29, 0.30 to 0.39, and 0.40 to 0.49 and ages lower or equal to 60 years and of 80 years were simulated for each genotype (CYP3A5*1 carriers and CYP3A5*1 non-carriers). Upper panels: CYP3A5*1/carriers. Lower panels: CYP3A5 *1/non carriers. Lower and upper box limits represent the first and the third quartile, respectively. Outliers are not shown. The middle solid line is the median. Dashed lines of 5- and 10-ng/mL indicate the therapeutic range considered in our hospital.

FIGURE 4

Box plots of AUC₂₄ simulated values on day 5 from the start of the once-daily doses of 5, 5.5, 6, 6.5, 7, and 7.5 mg of the ER-Tac formulation (corresponding to 0.07, 0.08, 0.09, 0.093, 0.100, and 0.110 mg/kg for a typical patient of 70-kg body weight; i.e., the mean value of the target population). Concentrations of patients with hematocrit levels ranging from 0.22 to 0.29, 0.30 to 0.39, and 0.40 to 0.49 and ages lower or equal to 60 years and of 80 years were simulated for each genotype (CYP3A5*1 carriers and CYP3A5*1 non-carriers). Upper panels: CYP3A5*1/carriers. Lower panels: CYP3A5*1/non carriers. Lower and upper box limits represent the first and the third quartile, respectively. Outliers are not shown. The solid middle line is the median.