OBJECTIVE: To evaluate the
population pharmacokinetic characters of orally administered cyclosporine A (CsA) from routine drug monitoring data after renal transplantation for readjusting individual dosage. METHODS: Routine Monitoring CsA population data retrospectively collected from renal transplantation out-patient were investigated by
NONMEM program. There were 1468 steady-state trough CsA concentrations and associated daily
dosage (mg.d-1) from 745 outpatients in our hospital. Michaelis-Menten
model was applied as basic pharmacokinetic model. Interindividual variability of Km and Vm, and the intraindividual variability were estimated with logarithmic additive model. The effect of dosage (DOSE), period after operation (POD), body weight (BW), preparation (PP), gender(GEN) and concurrent use of drug (DG) on pharmacokinetic
parameters were evaluated with structural parameter models. RESULTS: Michaelis-Menten model fitted better than one compartment linear non-steady-state and one compartment linear mean-steady-state model in routine monitoring steady-state trough concentration of CsA. Good fitness was obtained in predictive performance group (n=216) using population pharmacokinetic parameters estimated from index group (n=529). The final model and parameters of total data set were: The typical Vm(mg·d-1)=601× POD-0.21 ×BW0.139 × (1+GEN × 0.0778)×(1-PP × 0.0731), where GEN=0 as female and GEN=1 as male; PP=0 as aromatic water preparation and PP=1 as capsule preparation. The typical Km(mg·L-1) =2120 × (DOSE/235)-1.67× POD-0.651 × (1+DG1× 0.17) × (1+DG2 × 0.13), where DG1=1 as the concurrent use of Tabellae Multiglycosidorum Triptergii; and DG2=1 as comediation of Baoshenpian. The interindividual variability of Km and Vm were 24. 1% and 11.7% respectively. The Intraindividual variability was 13.4%. The mean absolute percent error of steady-state trough CsA concentrations between predicted and observed values were 7.72 ± 6.60%.CONCLUSION: Daily dosage of CsA and period after operation of renal transplantation have very significent effect on Michaelis-Menten model parameters. An good fitness was derived from the population model that should provide a new approach for clinical adjustment of oral CsA dosage.
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