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

Background:Accumulating studies on computational fluid dynamics (CFD) support the involvement of hemodynamic factors in artery stenosis. Based on a patient-specific CFD model, the present study aimed to investigate the hemodynamic characteristics of transplant renal artery stenosis (TRAS) and its alteration after stent treatment.Methods:Computed tomography angiography (CTA) data of kidney transplant recipients in a single transplant center from April 2013 to November 2014 were reviewed. The three-dimensional geometry of transplant renal artery (TRA) was reconstructed from the qualified CTA images and categorized into three groups: the normal, stenotic, and stented groups. Hemodynamic parameters including pressure distribution, velocity, wall shear stress (WSS), and mass flow rate (MFR) were extracted. The data of hemodynamic parameters were expressed as median (interquartile range), and Mann–Whitney U-test was used for analysis.Results:Totally, 6 normal, 12 stenotic, and 6 stented TRAs were included in the analysis. TRAS presented nonuniform pressure distribution, adverse pressure gradient across stenosis throat, flow vortex, and a separation zone at downstream stenosis. Stenotic arteries had higher maximal velocity and maximal WSS (2.94 [2.14, 3.30] vs. 1.06 [0.89, 1.15] m/s, 256.5 [149.8, 349.4] vs. 41.7 [37.8, 45.3] Pa at end diastole, P = 0.001; 3.25 [2.67, 3.56] vs. 1.65 [1.18, 1.72] m/s, 281.3 [184.3, 364.7] vs. 65.8 [61.2, 71.9] Pa at peak systole, P = 0.001) and lower minimal WSS and MFRs (0.07 [0.03, 0.13] vs. 0.52 [0.45, 0.67] Pa, 1.5 [1.0, 3.0] vs. 11.0 [8.0, 11.3] g/s at end diastole, P = 0.001; 0.08 [0.03, 0.19] vs. 0.70 [0.60, 0.81] Pa, 2.0 [1.3, 3.3] vs. 16.5 [13.0, 20.3] g/s at peak systole, P = 0.001) as compared to normal arteries. Stent implantation ameliorated all the alterations of the above hemodynamic factors except low WSS.Conclusions:Hemodynamic factors were significantly changed in severe TRAS. Stent implantation can restore or ameliorate deleterious change of hemodynamic factors except low WSS at stent regions.