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Antimicrobial Agents and Chemotherapy, July 2009, p. 2892-2901, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01193-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Modeling the Autoinhibition of Clarithromycin Metabolism during Repeated Oral Administration
Khaled Abduljalil,1,
Martina Kinzig,2
Jürgen Bulitta,2,
Stefan Horkovics-Kovats,3
Fritz Sörgel,2,4*
Michael Rodamer,2 and
Uwe Fuhr1
Department of Pharmacology, Clinical Pharmacology, University Hospital, University of Cologne, Cologne, Germany,1 IBMP—Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany,2 Sandoz GmbH, Kundl, Austria,3 Department of Pharmacology, University of Duisburg—Essen, Universitätsklinikum Essen, Essen, Germany4
Received 8 September 2008/ Returned for modification 30 January 2009/ Accepted 22 April 2009
Clarithromycin decreases CYP3A4 activity and thus gradually inhibits its own metabolism as well as that of coadministered drugs. The aim of this study was to obtain an understanding of the time course of these changes. The plasma concentration-time profiles of clarithromycin and its active metabolite, 14(R)-hydroxy-clarithromycin, in 12 young healthy volunteers after oral administration of a clarithromycin suspension (500 mg twice a day [b.i.d.] for seven doses) were modeled by population pharmacokinetic analysis in the NONMEM program. The nonlinearity of clarithromycin metabolism was considered during model development, and the metabolite disposition kinetics were assumed to be linear. The absorption kinetics of clarithromycin were best described by a Weibull function model. The pharmacokinetics of clarithromycin and its 14(R)-hydroxyl metabolite were adequately described by a one-compartment model each for clarithromycin and its metabolite as well as an inhibition compartment that reflects the autoinhibition of clarithromycin metabolism. Up to 90% of the apparent total clarithromycin clearance (60 liters/h) was susceptible to reversible autoinhibition, depending on the concentration in the inhibition compartment. The proposed semimechanistic population pharmacokinetic model successfully described the autoinhibition of clarithromycin metabolism and may be used to adjust the doses of other drugs that are metabolized by CYP3A4 and that are coadministered with clarithromycin. Simulations showed that for the standard dose of 500 mg b.i.d., no further increase in the level of exposure occurs after approximately 48 h of treatment. For a 1,000-mg b.i.d. dose, the achievement of steady state is expected to take several days and to achieve a 3.6-fold higher level of clarithromycin exposure than the 500-mg b.i.d. dose. This evaluation provides a rationale for safer and more effective therapy with clarithromycin.
* Corresponding author. Mailing address: Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, 90562 Nürnberg-Heroldsberg, Germany. Phone: 49-911-51 82 80. Fax: 49-911-51 82 828. E-mail: ibmp{at}osn.de
Published ahead of print on 4 May 2009.
Present address: Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, United Kingdom.
Present address: Ordway Research Institute, Albany, NY 12208.
Antimicrobial Agents and Chemotherapy, July 2009, p. 2892-2901, Vol. 53, No. 7
0066-4804/09/$08.00+0 doi:10.1128/AAC.01193-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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