Non-linear pharmacokinetic modelling of intravenous elgodipine

Objective, subjects and methods: The 1,4-dihydropyridine elgodipine was given as continuous infusion at various rates (5, 10, 15, 20, 40 μg/kg/h for 48, 48, 48, 24, or 6 h, respectively) to five groups of 6 - 12 healthy male subjects (total 42). Elgodipine plasma concentrations were measured with HPLC in 20 - 24 samples from each subject. Concentrations increased overproportionally with dose. Non-compartmental and compartmental evaluations were made. A two-compartment model with tag time and Michaelis-Menten term for elimination was found to be appropriate. Results: Based on Michaelis-Menten parameters and concentration time courses during infusions, the elimination appeared to be saturated already at low dosages. There appeared to be two distinct subpopulations with two-fold differences in the maximal elimination velocity. In 9/42 subjects, more frequently in the groups with lower infusion rates, the model failed and the Michaelis-Menten term had to be replaced with a constant rate to fit. A dose-dependent increase in the volume of distribution and differences in and difficulties with estimations of the Michaelis-Menten constant KM might indicate a non-linear plasma protein binding. The transfer rate constants to or from the peripheral compartment correlated with blood hemoglobin or creatinine and bilirubin concentrations, respectively. Conclusion: The results indicated that tissue distribution and protein binding had marked influence on the plasma concentrations and, thus, attenuated the impact of saturation in the elimination.