Time-dependent Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective

TL;DR

This study used population pharmacokinetic modeling to analyze long-term data from renal transplant patients, identifying key factors influencing cyclosporine clearance over time to improve individualized therapy.

Contribution

It provides a comprehensive model of time-dependent cyclosporine clearance incorporating multiple covariates, aiding personalized dosing strategies.

Findings

Body size, hematocrit, and haplotype significantly affect clearance.

Clearance decreases over time post-transplantation.

Dose adjustments are recommended based on patient-specific factors.

Abstract

Aim The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterise time-dependent clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modelling of long-term follow-up data from our institution. Methods In total, 3,674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analysed using nonlinear mixed-effects modelling. The effects of potential covariates were selected according to a previous report and well-accepted theoretical mechanisms. Model-informed individualised therapeutic regimens were also conducted. Results A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (5%). Allometrically scaled body size, haematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CsA dose adjustments should be considered in different postoperative periods. Conclusions By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimise CsA therapy.