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A comparative bioavailability study of the antituberculosis drugs isoniazid, rifampin, and pyrazinamide was carried out in a group of 10 healthy volunteers after administration of the three compounds, once in individual association and once in a combined, fixed preparation. The investigation was designed as an open, crossover study where each subject received five tablets of a preparation containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide (corresponding to a total dose of 250 mg isoniazid, 600 mg rifampin, and 1,500 mg pyrazinamide). The same doses were administered in the session where the drugs were combined using the individual formulations. For each subject and experimental session, 15 blood samples were collected over a period of 24 h, and the plasma concentrations of the three drugs were assessed. The results indicated the absence of negative pharmacokinetic interactions between the drugs when administered in both free and this new, fixed combination.

The time course of the plasma concentrations of isoniazid, rifampin, and pyrazinamide 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 combination of the same drugs. The blood kinetics of the three antituberculosis drugs 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 well-known 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, the levels on these days no differing from each other.(ABSTRACT TRUNCATED AT 250 WORDS)

The bioavailability of isoniazid, rifampin, and pyrazinamide in 2 combined formulations of the 3 drugs (Rifater) for use primarily in the short-course chemotherapy of tuberculosis has been studied in Chinese patients in Singapore and Hong Kong. One formulation, containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide per tablet is suitable for daily use, whereas the other, containing higher proportions of isoniazid and pyrazinamide, is designed for intermittent treatment, each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide. Appropriate dosages for the Chinese patients, whose average weight was approximately 50 kg, were 5 and 6 tablets, respectively. Plasma concentrations of the 3 drugs after giving such dosages of the 2 combined formulations were compared in 16 patients, 8 in Singapore and 8 in Hong Kong, by means of a crossover study, with the concentrations obtained when identical doses of the 3 drugs were given using standard separate drug formulations. The concomitant urinary excretions of the drugs and their major metabolites were also estimated. Very similar results were obtained whether the drugs were given as the combined preparations or in their standard separate formulations, demonstrating the excellent bioavailability of all 3 drugs in each of the 2 combined formulations.

The absorption and metabolism of streptomycin, isoniazid, rifampicin, and pyrazinamide were evaluated after administration of each drug alone and in combination. In the combination sessions, isoniazid, rifampicin, and pyrazinamide were administered orally, either individually or in a single fixed-ratio triple preparation. The results have shown that the pattern of absorption and metabolism (acetyl-isoniazid, desacetyl-rifampicin, and pyrazinoic acid) found after administration of each drug alone did not differ from that found after administration of the drugs in free and fixed combination. The 3 orally administered drugs given in a fixed combination resulted in a reduction of the order of 50% of the total number of tablets to be ingested.