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Comparison of methods to calculate cyclosporine a bioavailability from consecutive oral and intravenous doses

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Abstract

The pharmacokinetics of cyclosporine A (CyA) was studied in 21 uremic patients. The plasma concentrations after an oral dose and a subsequent short-term infusion were analyzed simultaneously by nonlinear regression. Bi- and triexponential disposition models with either zero- or first-order absorption were fitted to the data. A triexponential disposition model with zero-order absorption was generally found to best describe the concentration-time profile. The bioavailability and clearance were estimated to be 0.24±0.10 and 21±8 L/hr, respectively. These values differed only marginally from those predicted by the other models. Similar bioavailability estimates were also obtained from a three-compartment model where elimination was assumed saturable, from a deconvolution procedure, and from analyses based on blood concentrations. Markedly higher bioavailabilities (0.34±0.13) were obtained when a model-independent AUCcorrection procedure, commonly used to calculate CyA bioavailability, was used. The difference could not be explained by poor description of data in the model-dependent analyses, but rather by overestimation in the model-independent analyses mainly due to errors in the extrapolations used. Thus, by the simultaneous fitting procedure, which is a new approach for estimating CyA bioavailability, drawbacks of the AUCcorrection procedure could be avoided. Further, future studies of CyA bioavailability could be designed with a markedly shorter and more convenient length of time if analyzed by the proposed method.

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  1. Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Uppsala, Box 580, S-751 23, Uppsala, Sweden

    Mats O. Karlsson & Agneta Lindberg-Freijs

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  1. Mats O. Karlsson
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Karlsson, M.O., Lindberg-Freijs, A. Comparison of methods to calculate cyclosporine a bioavailability from consecutive oral and intravenous doses. Journal of Pharmacokinetics and Biopharmaceutics 18, 293–311 (1990). https://doi.org/10.1007/BF01062270

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  • DOI: https://doi.org/10.1007/BF01062270

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