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 (Km) 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 (Vmax) remained constant. The following parameters with interindividual variation in parenthesis were estimated: Vmax = 852 mg/24 hr (43%) and Km 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.
Department of Surgery, University of Texas Medical School.
J
J
Grevel
B K
BK
Post
B D
BD
Kahan
D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008657:Metabolic Clearance Rate; D015233:Models, Statistical; D011159:Population Surveillance
D016572:Cyclosporine