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

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

doi:10.1002/cpt.778

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

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

Research output: Contribution to journal › Article › peer-review

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 E_max 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.

Original language	English
Pages (from-to)	674-683
Number of pages	10
Journal	Clinical Pharmacology & Therapeutics
Volume	103
Early online date	7 Aug 2017
DOIs	https://doi.org/10.1002/cpt.778
Publication status	Published - Apr 2018

Keywords

Rifampin
Tuberculosis
Pharmacokinetics
Modeling
Nonlinear models

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10.1002/cpt.778Licence: CC BY-NC

Svensson-2017-A-population-CPT-CC
Copyright 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Final published version, 996 KBLicence: CC BY-NC

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title = "A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses",

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.",

keywords = "Rifampin, Tuberculosis, Pharmacokinetics, Modeling, Nonlinear models",

author = "Svensson, {Robin J.} and Aarnoutse, {Rob E.} and Diacon, {Andreas H} and Rodney Dawson and Gillespie, {Stephen H.} and Boeree, {Martin J.} and Simonsson, {Ulrika S. H.}",

note = "The research leading to these results has received funding from the Swedish Research Council in addition to the Innovative Medicines Initiative Joint Undertaking (www.imi.europe.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in kind contribution.",

year = "2018",

month = apr,

doi = "10.1002/cpt.778",

language = "English",

volume = "103",

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AU - Svensson, Robin J.

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AU - Gillespie, Stephen H.

AU - Boeree, Martin J.

AU - Simonsson, Ulrika S. H.

N1 - The research leading to these results has received funding from the Swedish Research Council in addition to the Innovative Medicines Initiative Joint Undertaking (www.imi.europe.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

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N2 - 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.

AB - 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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KW - Tuberculosis

KW - Pharmacokinetics

KW - Modeling

KW - Nonlinear models

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ER -

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

Abstract

Keywords

UN SDGs

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