Model-Informed Dosage Optimization Of Tacrolimus In Primary Nephrotic Syndrome Patients

ObjectivesThis study aimed to evaluate the predictive performance of published tacrolimus population pharmacokinetic（Pop PK）models for primary nephrotic syndrome（PNS）patients and to establish a Pop PK model of tacrolimus in patients with PNS based on a prospective research,and then the dose optimization was guided based on the model.MethodsThis study was a prospective trial conducted in the Third Xiangya Hospital of Central South University from September 2020 to March2022.The subjects were PNS patients treated with tacrolimus orally.Nonlinear mixed-effects modeling（NONMEM）was used for population pharmacokinetic analysis.（1）Data on published tacrolimus Pop PK models for PNS patients was extracted from the literature,and model predictability was evaluated with prediction-based and simulation-based diagnostics and Bayesian forecasting;（2）The demographics,clinical data,concomitant medications and genetic genotypes of patients were collected and screened as covariates to evaluate the effects of these factors on the pharmacokinetic parameters of tacrolimus,and a Pop PK model（XY3-Pop PK）was constructed.This model was evaluated by a bootstrap method,goodness-of-fit plot and visual predictive check.Monte Carlo simulation was used to optimize the tacrolimus dose.Results（1）223 tacrolimus concentrations from 50 patients were prospectively collected as an external validation dataset.In prediction-based evaluation,none of the 11 identified published Pop PK models of tacrolimus had met a predefined criteria of a median prediction error≤±20%and a median prediction error≤30%.In simulation-based diagnostics,visual predictive check indicated large discrepancies between the observations and simulations.Bayesian prediction demonstrated amelioration in the model predictability with the inclusion 2-3 prior observations.（2）A total of 500 concentrations of 101 patients were prospectively collected for the establishment of XY3-Pop PK.The one compartment model with first-order absorption kinetics can fully describe the pharmacokinetics of tacrolimus.Fifty covariates were screened,among which Wuzhi capsule and CYP3A5 rs776746 had a significant effect on the clearance（CL）of tacrolimus（P<0.001）.The CL of tacrolimus was 13L h^-1,and the between-subject variability was 29.2%.The CL of patients with CYP3A5*1/*1 and*1/*3 were 2.21-fold and 1.485-fold higher compared to patients with*3/*3,respectively.The CL of tacrolimus in patients receiving Wuzhi capsule was 42.9%of that in patients without Wuzhi capsule.The final model formula is:Ka=7.37 h^-1;CL(L h^-1)=13×CLcov×exp（ηi）;V（L）=258.The estimated parameters of the original model was in the 95%confidence interval（2.5%-97.5%）of parameters in the bootstrap procedure.Goodness-of-fit plots showed good global fit,and most of the conditional weighted residuals were distributed within±2.The observations and simulations have similar distribution characteristics in visual prediction check.Monte Carlo simulation results showed that the target tacrolimus concentration range of 3-8ng/ml can be reached for CYP3A5*3/*3 patients with tacrolimus1mg q12h（without wuzhi capsule）or 0.5 mg q12h（with wuzhi capsule）.ConclusionsThe published tacrolimus Pop PK models showed large prediction error in the external validation study.The established XY3-Pop PK model is stable and conducive to the individualized treatment of tacrolimus.