Application of a Gamma Model of Absorption to Oral Cyclosporin

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Abstract
Background: Some drugs, such as cyclosporin, exhibit flat and delayed absorption profiles, with a correlation between the delay and the peak width. Such profiles can be described by an absorption model in which the absorption rate is derived from a gamma distribution (of which the classical first-order absorption model is a special case). Objective: To develop a model for the pharmacokinetics of extravascular administration of cyclosporin and apply it to a study of the pharmacokinetics of cyclosporin microemulsion in stable renal transplant recipients. Patients and participants: 21 renal transplant patients receiving oral cyclosporin microemulsion 75 to 175mg twice daily. Methods: The equation of the plasma concentration-time curve after oral administration was expressed as a convolution product between the absorption rate and a multi-exponential impulse response. The convolution integral was computed analytically and expressed in terms of the incomplete gamma function. Cyclosporin was assayed by liquid chromatography/mass spectrophotometry. The model was fitted by nonlinear regression, using a specially developed program. Results: The gamma model yielded a good fit in all of the 21 patients studied. Attempts to fit the same data by a classical exponential with lag-time model failed in most patients. Conclusions: This model could simplify the Bayesian monitoring of cyclosporin therapy.