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Setting: Mulago Hospital, Kampala, Uganda., Objective: To evaluate the usefulness of urine dipsticks for monitoring adherence to anti-tuberculosis chemotherapy., Design: In-house urine dipsticks for detection of isoniazid (INH) metabolites were compared to commercial test strips. The value of n-butanol to detect rifampicin was compared to coloration of the urine. Non-adherence was assessed through a questionnaire and reviews of the Mulago Hospital TB register., Results: Urine was obtained from 236 patients (127 adults and 109 children) on daily chemotherapy. Using commercial test strips as standard, the sensitivity of in-house urine dipsticks was 99.5% and specificity was 96.4%. The sensitivity and the specificity of n-butanol and of coloration of urine to detect rifampicin were low (64.0% and 54.9%, and 85.5% and 64.8%, respectively). Fifty patients (21.2%) admitted non-adherence to treatment during the previous month. An additional 15 (6.8%) were detected through urine testing. Of 911 patients in the TB register of Mulago Hospital who had started treatment in the first 3 months of 2000, 39.7% did not complete their treatment. Two-thirds of these had discontinued treatment in the first 2 months., Conclusion: In-house INH test strips are as effective as commercially available strips for detecting isoniazid in the urine. They are a simple tool for monitoring adherence. Adherence to anti-tuberculosis chemotherapy as determined by the use of isoniazid test strips and review of the TB register showed poor compliance. Tests for rifampicin are less sensitive and specific.

Setting: The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations., Objective: To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations., Design: A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6 and 8 hours after each drug administration using a high performance liquid chromatography (HPLC) method. The rifampicin and desacetylrifampicin content of complete urinary collections made from 0-4 and 4-8 hours after dosage were determined using both the HPLC and a much simpler colorimetric procedure., Results: There was good agreement between the relative bioavailability of the formulations using plasma and urinary excretion data, although the precision of the urinary-based estimates was slightly less than those derived from the plasma findings. There was also good agreement between the HPLC and colorimetric estimates of the combined urinary excretion of rifampicin plus desacetylrifampicin., Conclusions: Urinary excretion data may be used for ongoing quality control to confirm that commercial combined rifampicin-containing formulations that were initially shown to be satisfactory continue to be so.

Setting: The perceived need to demonstrate whether or not the rifampicin bioavailability of commercially manufactured fixed-dose combinations is satisfactory., Objective: To establish an international laboratory network to assess rifampicin bioavailability., Design: Convenient assay kits were devised to evaluate the ability of laboratories in China, India, Italy, South Africa, Thailand and the USA to determine plasma and urinary concentrations of rifampicin and desacetyl-rifampicin., Results: Five laboratories, all of whom used high pressure liquid chromatographic methods, were shown to be able to accurately and precisely determine the two compounds., Conclusion: Such a procedure is simple, convenient and objective and could be further employed to enlarge the intended international laboratory network.

Setting: The benefits of fixed-dose combination (FDC) formulations of rifampicin, isoniazid and pyrazinamide over individual formulations are well recognised., Objectives: To evaluate the comparative bioavailability of antituberculosis drugs in FDC formulations and the same doses in separate formulations of antituberculosis drugs, using a simplified protocol developed by the World Health Organization (WHO)., Methods: Twenty healthy volunteers were included in the study and evaluated for bioequivalence of rifampicin in a cross-over experimental design. After administration of drugs the plasma concentration of rifampicin and desacetyl-rifampicin was measured repeatedly up to 8 hours in both plasma and urine. Various pharmacokinetic parameters of rifampicin, such as Cmax, Tmax, elimination rate constant, area under the curve (AUC) up to 8 hours and absorption efficiency were calculated., Results: No significant differences were observed between the FDCs and separate formulations when Cmax, Tmax, AUC and absorption efficiencies were compared by parametric test and Hauschke's analysis., Conclusion: The WHO simplified protocol is suitable for evaluating bioequivalence of antituberculosis drugs.

Setting: The present study assesses bioavailability indices for rifampicin, isoniazid and pyrazinamide when administered to healthy volunteers separately or in a fixed triple-drug formulation, Rifater 125 SCT., Objective: To compare the pharmacokinetics of rifampicin, isoniazid and pyrazinamide based on their blood concentrations up to 12 hours with the proportions of the doses of the drugs and their metabolites excreted in urine up to 12 hours, and to assess the bioavailability indices for the free and fixed triple drug formulations., Design: An open cross-over study was conducted in 18 healthy volunteers with normal hepatic and renal functions to whom the drug combinations were administered in free and fixed dose formulations a week apart, to the same subject., Results: Concentrations of the three drugs/metabolites were assessed in blood and urine. The results indicated the absence of negative pharmacokinetic interactions between the drugs when administered in both the free and the new fixed triple drug formulation., Conclusion: Human bioavailability studies provide direct straightforward information, particularly when studying compounds such as rifampicin and other major anti-tuberculosis drugs. The results of the present study indicate that the pharmacokinetic properties of rifampicin, isoniazid and pyrazinamide as assessed after individual and combined administration do not change when combined in a single pharmaceutical preparation. The bioavailability indices calculated based on plasma concentrations and urinary levels for all three drugs compared well.