Enliven: Surgery and Transplantation

Objectives:
Equoral® is a generic formulation of cyclosporine widely used in Tunisian renal transplant patients. The purposes of this study were to explore the
pharmacokinetic variability of Equoral® in Tunisian renal transplant, to develop a population pharmacokinetic model and a MAP-BE of Equoral®
PK parameters and global exposure.

Methods:
Full-PK profiles were obtained from 17 renal transplant patients given Equoral® twice-daily. Measurements were performed using an FPIA
technique. To estimate popPK parameters of cyclosporine, a non linear mixed effects approach was used and the popPK parameters were used as
priors to develop a MAP-BE for estimation of Equoral® PK parameters and AUC using three blood concentrations. Predictive performances were
tested by calculating mean predicted error between estimated and reference AUC. The validation of these PK tools was performed using jackknife
approach, visual predictive check and bootstrapping method.

Results:
Equoral® exhibited a high inter-patient variability: C0= 90±57 ng/mL, Cmax = 762±343 ng/mL and AUC0-12 = 2460±1240 ng.h/mL. A two compartment
model with Erlang distribution best described the data: residual proportional error was 26.8% and imprecision parameter estimate was less than 26%.
None of the tested covariates significantly affected cyclosporine pharmacokinetics. Using this model and cyclosporine concentrations measured at
0.30 and 180min post-dose, MAP-BE could accurately estimate cyclosporine AUC, mean bias between estimated and reference AUC was 5.47 ±
29% with 82% of the patients with AUC bias < 20%. The doses proposed by the BE were similar to those proposed using all concentrations in 14
out of 17 patients.

Conclusion:
A popPK model for Equoral® when given to Tunisian kidney recipients. A MAP-BE using only three blood concentrations that estimates accurately
Equoral® exposure in these patients was developed and could allow dose adjustments based on the AUC in clinical setting.