Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

Abstract

AIMSVarious mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODSThe external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction-and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTSFifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction-and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between British Journal of Clinical Pharmacology Br J Clin Pharmacol (2019) 85 746-761 746 the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONSThe published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Population pharmacokinetic analyses are widely used to describe mycophenolate mofetil pharmacokinetic characteristics in adult kidney transplant recipients co-administered with tacrolimus and facilitate dose individualization. • Model transferability can be influenced by centre-related factors, and it is unclear whether these models can be appropriately extrapolated to other centres. WHAT THIS STUDY ADDS• We comprehensively evaluated the external predictability of published models using an independent dataset.• The published models performed unsatisfactorily in prediction-and simulation-based diagnostics.• The investigation of the impact of model structure did not show that incorporating the EHC process could improve predictive performance. External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 747 External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 749 External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 759

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

“…Frequent AUC estimation has been suggested in cyclosporine-cotreated cohorts: “in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year.” 33 This is due to a 30%–50% increase in dose-normalized exposure over the first 3 months, to avoid overshooting target. However, without the dose-dependent inhibitory effect of cyclosporine on EHC, the change in exposure over the first 3 months appears less substantial in tacrolimus-containing regimens, 121,149 and thus a lesser frequency should suffice.…”

Systematic external evaluation of reported population pharmacokinetic models of vancomycin in Chinese children and adolescents

“…The median prediction error (MDPE) and median absolute prediction error (MAPE), and PE% within ±20% ( F 20 ) and PE% within ±30% ( F 30 ) were calculated to assess the accuracy and precision of the model. The predictive performance of a candidate model was considered satisfactory if the investigated models met all the standards (MDPE ≤ ±20%, MAPE ≤30%, F 20 ≥35%, and F 30 ≥ 50%) 9,11,18 …”

“…10 Moreover, it might be cost-effective to screen the most appropriate PopPK model for optimizing dosage regimens than to describe a new model. 11 Lo et al recommended that a more reliable method is to substitute the original data into each model for analysis and then compare the parameter estimates of each model. 12 Therefore, it is necessary to verify the predictability of the published models dosage.…”

“…The predictive performance of a candidate model was considered satisfactory if the investigated models met all the standards (MDPE ≤ ±20%, MAPE ≤30%, F 20 ≥35%, and F 30 ≥ 50%). 9,11,18 (1) PE % = pred − obs obs × 100 where "ipred i " is the individual predicted value of the ith patient, and "obs i " is the observed value of the ith patient.…”

“…Marsot et al conducted a review of twenty‐five population pharmacokinetic models of vancomycin developed in the past few decades, and they suggested that conducting an external evaluation should be the first step in the pharmacokinetic analysis of vancomycin rather than describing a new model 10 . Moreover, it might be cost‐effective to screen the most appropriate PopPK model for optimizing dosage regimens than to describe a new model 11 . Lo et al recommended that a more reliable method is to substitute the original data into each model for analysis and then compare the parameter estimates of each model 12 .…”