Title: Investigation on Circadian and age-Dependent Variations In Cyclosporine (Csa) Concentration Distributions In Liver Transplant Patients
Abstract: A comparative population pharmacokinetic analysis was performed on CsA concentrations, “as withdrawn” in clinical setting, from a learning group of liver transplant patients. Twenty patients (8 adults and 12 children) who were on Neoral® post-ortothopic liver transplantation over 2004 to 2009 were studied. All patients received Neoral® twice daily orally at 08:00 AM and at 08:00 PM. Whole blood CsA concentrations were measured by FPIA (Abbott Diagnostics). C0 drug concentrations were recorded in morning (C0AM) and in evening before each dosing (C0PM) and C2 concentrations - in morning and in evening 2 hours post-dosing (C2AM and C2PM). A total of 323 CsA C0 in children group and 242 C0 in adult group and a set of 117 CsA C2 in children group and a set of 133 C2 in adult group were analyzed. Population pharmacokinetic analysis was performed with dose normalized to 1mg/kg cyclosporine concentrations in order to avoid body weight (BW) differences between the 2 age groups. No circadian differences in drug concentrations in both populations were observed. All drug concentration distributions were skewed to the right. The measures of central tendency showed statistically significant higher estimates for adult group. Normalized CsA C0 at Day 2 after liver transplantation in adult patients correlated significantly with measured Scr levels (r = 0.62, P = 0.031). The findings can’t be explained by body weight between group’s differences since normalized cyclosporine concentrations were used. We expect that age-related nongenomic factors, controlling cyclosporine metabolism and distribution, could be a plausible reason.