Comparative Bioavailability of Isoniazid, Rifampin, and Pyrazinamide Administered in Free Combination and in a Fixed Triple Formulation Designed for Daily Use in Antituberculosis Chemotherapy: II. Two-Month, Daily Administration Study

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Abstract
The time course of the plasma concentrations of isoniazid, rifampin, and pyrazlnamide was assessed in a group of 13 patients with lung tuberculosis treated over a period of 2 months on a continuous daily basis with a fixed triple concentration of the same drugs. The blood kinetics of the three antituberculosis drug were determined on Days 1, 15, 30, and 60 of treatment. The triple combination employed in this study contained 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide per tablet, the number of tablets ranging from four to seven per day according to the body weight of the patients. Almost superimposable plasma concentration curves for isoniazid were observed during the 4 days of the study. For rifampin, a fall in the plasma concentrations at the time intervals after the peak was observed comparing the data on Day 1 with those on Days 15, 30, and 60, which did not differ from each other. This finding is thought to be due to the wellknown phenomenon of self-induction, which leads to an increased rate of disposal of the antibiotic from the blood compartment within the first and second weeks of continuous treatment. For pyrazinamide, an equilibrium in the opposite sense as that of rifampin seemed to take place within the 2 months of the study. Because of the relatively high plasma levels observed 24 h after each administration, an increase in plasma concentrations with respect to those observed on Day 1 was found on Days 15, 30, and 60, levels on these days not differing from each other. No progressive cumulative effect over that seen between Day 1 and Day 15 was therefore observed. The results of the present study indicate that no major changes in the blood kinetics of isoniazid, rifampin, and pyrazinamide are observed when the three antituberculosis drugs are administered orally in a fixed triple combination over a period of time corresponding to that of the initial intensive phase of short-course antituberculosis chemotherapy.

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