  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.
