Incorporating Nonlinear Kinetics to Improve the Predictive Performance of Population Pharmacokinetic Models for Ciclosporin in Adult Renal Transplant Recipients: A Comparison of Modelling Strategies

Abstract

Aim: Ciclosporin (CsA) has been shown to follow nonlinear pharmacokinetics in renal transplant recipients who received Neoral-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population pharmacokinetic (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability. Methods: A total of 2969 CsA whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction-based and simulation-based diagnostics (prediction- corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. Results: Model predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance over that of the other three compartmental models. The saturated binding of CsA to erythrocytes, and auto-inhibition that arose from the inhibitory effects of CsA on CYP3A4/P-gp and CsA-prednisolone drug interaction may have contributed to the nonlinearity. Conclusions: Incorporating nonlinear properties are likely to be a promising approach for improving CsA model predictability. However, CsA nonlinear kinetics resources need further investigation. Until then, Michaelis-Menten empirical model can be used for CsA dose adjustments.

Population pharmacokinetics of ciclosporin in allogeneic hematopoietic stem cell transplant recipients: C‐reactive protein as a novel covariate for clearance

“…CsA DD was identified as a significant covariate for CL, which declined with the decrease of CsA DD. This tendency was also observed in the previous studies, which indicated nonlinear clearance of the drug 31,32 . Such nonlinear kinetics phenomenon may be partially due to the saturated distribution into red blood cells or the inhibitory effects of CsA on CYP3A4/P‐glycoprotein 31 .…”

“…This tendency was also observed in the previous studies, which indicated nonlinear clearance of the drug. 31,32 Such nonlinear kinetics phenomenon may be partially due to the saturated distribution into red blood cells or the inhibitory effects of CsA on CYP3A4/P-glycoprotein. 31 Further studies with intensive sampling are needed to explore the nonlinear kinetics phenomenon of CsA.…”

Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective

“…CsA exposure in the early phases after transplantation was 15.4% lower than that in the stable period when the same CsA dose was administered. The increased CsA bioavailability in the initial period may correlate with improved absorption in the intestine [42] and co-administration with steroids [43], which can activate the pregnane X receptor (PXR) to upregulate CYP3A and P-gp activity [35,44]. Therefore, CsA dosage should be reduced when steroids are co-administered [20].…”