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A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses

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Author(s)

Robin J. Svensson, Rob E. Aarnoutse, Andreas H Diacon, Rodney Dawson, Stephen H. Gillespie, Martin J. Boeree, Ulrika S. H. Simonsson

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Abstract

Accumulating evidence suggest that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics and anti-mycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35 or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide and ethambutol in the second week.
This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using non-linear mixed effects modeling. The final population pharmacokinetic model included an enzyme turn-over model accounting for time-dependent elimination due to auto-induction, concentration-dependent clearance and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure-response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high dose rifampicin.
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Original languageEnglish
Pages (from-to)674-683
Number of pages10
JournalClinical Pharmacology & Therapeutics
Volume103
Early online date7 Aug 2017
DOIs
Publication statusPublished - Apr 2018

    Research areas

  • Rifampin, Tuberculosis, Pharmacokinetics, Modeling, Nonlinear models

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