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Antimicrobial Agents and Chemotherapy, June 2009, p. 2346-2353, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01120-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine{triangledown}

Min Zhu,{dagger} Sanjeev Kaul, Partha Nandy,{ddagger} Dennis M. Grasela, and Marc Pfister*

Bristol-Myers Squibb Research and Development, Princeton, New Jersey

Received 20 August 2008/ Returned for modification 15 November 2008/ Accepted 6 February 2009

Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.

* Corresponding author. Mailing address: Research and Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543-4000. Phone: (609) 252-5322. Fax: (609) 252-6313. E-mail: marc.pfister{at}bms.com

{triangledown} Published ahead of print on 17 February 2009.

{dagger} Present address: Amgen, Thousand Oaks, CA.

{ddagger} Present address: Johnson & Johnson, Raritan, NJ.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2346-2353, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01120-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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