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Antimicrobial Agents and Chemotherapy, August 2004, p. 2951-2957, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2951-2957.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Isoniazid Pharmacokinetics-Pharmacodynamics in an Aerosol Infection Model of Tuberculosis

Ramesh Jayaram, Radha. K. Shandil, Sheshagiri Gaonkar, Parvinder Kaur, B. L. Suresh, B. N. Mahesh,{dagger} R. Jayashree, Vrinda Nandi, Sowmya Bharath, E. Kantharaj,{ddagger} and V. Balasubramanian*

AstraZeneca India Pvt. Ltd., Hebbal, Bangalore 560 024, India

Received 3 March 2004/ Accepted 14 April 2004

Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73).

* Corresponding author. Mailing address: AstraZeneca India Pvt. Ltd., Bellary Rd., Hebbal, Bangalore 560 024, India. Phone: 91-80-23621212, ext. 130. Fax: 91-80-23621214. E-mail: bala.subramanian{at}astrazeneca.com.

{dagger} Present address: Novartis Institute for Tropical Diseases Pte. Ltd., Singapore 117528, Singapore.

{ddagger} Present address: Department of ADME/Tox, In Vitro Pharmacokinetics Group, Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica, 2340 Beerse, Belgium.

Antimicrobial Agents and Chemotherapy, August 2004, p. 2951-2957, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2951-2957.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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