MICHAELIS-MENTEN KINETICS DETERMINE CYCLOSPORINE STEADY-STATE CONCENTRATIONS - A POPULATION ANALYSIS IN KIDNEY-TRANSPLANT PATIENTS

Dosage adjustments of cyclosporine are confounded with an unexpected degree of variability, thus invalidating a direct proportionality between the oral dose rate and the steady-state concentration. In 1033 observations of dose rate and average steady-state concentration collected during therapeutic monitoring (area under the curve method) in 134 adult kidney transplant patients, a population pharmacokinetic analysis showed that a Michaelis-Menten model fitted the data better than a linear clearance model. It was further shown that the Michaelis-Menten constant (K(m)) parameter of the Michaelis-Menten model (the average steady-state concentration at half-maximal dose rate) increased during the first 4 months after transplantation whereas the maximal dose rate of the Michaelis-Menten model (V(max)) remained constant. The following parameters with interindividual variation in parenthesis were estimated: V(max) = 852 mg/24 hr (43%) and K(m) at 114 days after transplantation = 349 ng/ml (117%). An algorithm was derived from this population model that guides the clinician during the adjustment of oral cyclosporine dose rates.