2004 - Uppsala - Sweden

PAGE 2004: poster
Justin Wilkins

A population pharmacokinetic-enzyme model for rifampicin autoinduction and bimodal absorption in pulmonary tuberculosis patients

Justin J Wilkins (1), Grant Langdon (1), Helen McIlleron (1), Goonaseelan Pillai (2), Peter J Smith (1) and Ulrika SH Simonsson (3)

(1) Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; (2) Novartis Pharma, Basel, Switzerland; (3) Division of Pharmacokinetics and Drug Therapy, Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden

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Objectives: This study was designed to describe the pharmacokinetics of rifampicin in South African pulmonary tuberculosis patients on daily treatment with a standard rifampicin-containing drug regimen, using nonlinear mixed-effects modeling. In addition, the pharmacokinetic model was built to account for the considerable interindividual and interoccasional variability inherent in the drug's pharmacokinetic properties.

Methods: Three datasets containing 2 913 rifampicin plasma concentration-time data collected from 261 South African pulmonary tuberculosis patients were pooled. All subjects had been receiving rifampicin (7.01-15.78 mg/kg) once daily for 5 days per week, with a drug holiday on weekends, for at least 10 days. A mechanistic pharmacokinetic model encapsulating an enzyme turnover model to describe rifampicin's autoinductive properties and a mixture model to describe bimodality in the drug's absorption was developed using NONMEM. Parameters describing interindividual and interoccasional variability were included.

Results: The model comprised absorption, central plasma and enzyme pool compartments. The enzyme submodel was a positive feedback system – increases in rifampicin plasma concentration increased the enzyme production rate which accelerated the drug’s rate of elimination. Total clearance and volume of distribution were similar to published values for tuberculosis patients. The absorption rate constant was bimodal, being more than threefold faster in one subpopulation. The estimated enzyme turnover corresponded to an enzymatic half-life of approximately one day.

Conclusion: The model presented here describes the time course of autoinduction of rifampicin metabolism in tuberculosis patients and confirms the previously-reported phenomenon of bimodality in the drug’s absorption.




Reference: PAGE 13 (2004) Abstr 538 [www.page-meeting.org/?abstract=538]
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