Title:The Case for Using Higher Doses of First Line Anti-Tuberculosis Drugs to Optimize Efficacy
VOLUME: 20 ISSUE: 39
Author(s):Sylvain Goutelle, Laurent Bourguignon, Pascal Maire, Roger W. Jelliffe and Michael N. Neely
Affiliation:Hospices Civils de Lyon, Hopital Pierre Garraud, Service Pharmacie, 136 rue du Commandant Charcot 69005 LYON.
Keywords:Pulmonary tuberculosis, anti-tuberculosis drugs, dosage design, pharmacokinetics, pharmacodynamics.
Abstract:Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive
maximum benefit from current agents. However, the dosage of current anti-TB drug regimens has never been optimized according to
the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic,
experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis
treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that
patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent
dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher
doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely
that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes
such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of
isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline
anti-TB agents has definite potential for shortening or improving TB treatment.
