Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling

Abstract

Aims: The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models.

Methods: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting.

Results: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range.

Conclusion: A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Figure 1

(A) Observed tacrolimus concentrations (n = 3100) in 242 patients (prediction-corrected). Prediction-corrected visual predictive checks using (B) the Brisbane model, (C) the Oslo model and (D) the theory-based model. Red solid line median observed concentration; red dashed lines 5^th and 95^th percentiles of the observed concentrations; black solid line median predicted concentration in 100 simulated subsets of total dataset; black dashed lines 5^th to 95^th percentiles of the predicted concentrations. Grey-shaded areas represent 95% confidence intervals of the prediction percentiles

Figure 2

Prediction-corrected visual predictive check of tacrolimus concentrations using the theory-based model, shown over the range of the covariates; (A) haematocrit, (B) time after transplantation, (C) prednisolone dose and (D) fat free mass. Red solid line median observed concentration; red dashed lines 5^th and 95^th percentiles of the observed concentrations; black solid line median predicted concentration in 100 simulated subsets of total dataset; black dashed lines 5^th to 95^th percentiles of the predicted concentrations. Grey-shaded areas represent 95% confidence intervals of the prediction percentiles

Figure 3

Prediction error of the tacrolimus concentrations in the external evaluation dataset over time after transplantation, using the empirical Brisbane and Oslo models and the combined theory-based model. Time in days after transplantation are binned: The first bin reflects day 1 after transplantation, while the subsequent ten bins are generated from day 2–3, 4–5 and so on until day 20–21. The median prediction error in each bin (solid lines) is shown with 95% confidence interval (vertical lines). The shaded areas represent the interval covering 90% of the individual prediction errors in each bin (5^th to 95^th percentiles). () Brisbane model, () Oslo model, () theory-based model

Figure 4

(A) Concentration–time profiles in 1000 simulated individuals using covariate-based dosing (red) and the current standard initial dose regimen in Oslo (0.04 mg kg⁻¹ twice daily, blue). (B) Concentration–time profiles in 1000 simulated individuals using covariate-based dosing (red) and covariate-based dosing with Bayesian dose adaptation (green). All concentrations are standardized to a haematocrit of 45%, and the simulation includes higher bioavailability on the day of transplantation (day 0) and the day after transplantation (day 1). Thick lines median predicted concentration; dashed, coloured lines 5^th to 95^th percentiles of the predicted concentrations; dotted, horizontal lines suggested acceptable range for average steady-state concentration values, standardized to a haematocrit of 45% (11.4 to 17.8 μg l⁻¹); stars times of concentration measurement, Bayesian feedback and reduction in between subject variability