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Modification to improve efficiency of sampling schedules for BA/BE testing of FDC anti-tuberculosis drugs

Authors: Gabriels, G. A.1; McIlleron, H.1; Smith, P. J.1; Folb, P. I.2; Fourie, P. B.3

Source: The International Journal of Tuberculosis and Lung Disease, Volume 11, Number 2, February 2007 , pp. 181-188(8)

Publisher: International Union Against Tuberculosis and Lung Disease

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Abstract:

SETTING: The assessment of rifampicin (RMP) containing fixed-dose combination (FDC) formulations using in vivo bioequivalence testing is widely accepted. It would be advantageous for both the drug regulatory authorities and drug manufacturers, for optimum minimum blood testing time intervals that encompass all anti-tuberculosis active constituents in the FDC to be established.

OBJECTIVE: To determine the optimum blood sampling schedule for testing novel FDC anti-tuberculosis drugs, isoniazid, RMP, pyrazinamide and ethambutol

DESIGN: The results of 12 different single-dose, two-way cross-over designs are presented. The studies determined the bioavailability and bioequivalence of RMP-containing FDCs, and conformed with the requirements of the South African national drug regulatory authority for each of the active constituents.

RESULTS: The pharmacokinetic parameters to determine bioavailability and the Hauschke method to determine bioequivalence revealed that a six-point time protocol, namely 0, 1, 2, 4, 6 and 8 h, provides a good approximation of the area under the curve, and that an 11-point time protocol of 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h provided information comparable to the conventional 15 time-points for FDCs containing up to four drugs.

CONCLUSION: The findings provide concrete economic benefit and convenience for quality assurance testing of existing and novel FDCs.

Keywords: bioavailability; bioequivalence; fixed-dose combinations; sampling schedules; tuberculosis

Document Type: Regular Paper

Affiliations: 1: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Rondebosch, South Africa 2: Medical Research Council, Pretoria, South Africa 3: National Tuberculosis Research Programme, Medical Research Council, Pretoria, South Africa

Publication date: February 1, 2007

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.

    Certain IJTLD articles are selected for translation into French, Spanish, Chinese or Russian. They are available on the Union website

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