Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels

Abstract

Tuberculosis (TB) needs treatment with three to five different drugs simultaneously, depending on the patient category. These drugs can be given as single drug preparations or fixed dose combinations (FDCs) of two more drugs in a single formulation. World Health Organization and International Union against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. The relative bioavailability of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PYZ) was assessed on a group of 13 healthy male subjects from a four drug FDC versus separate formulations at the same dose levels. The study was designed to be an open, crossover experiment. A total of nine blood samples each of 3 ml volume were collected over a period of 24-h. The concentrations of RIF, its main metabolite desacetyl RIF (DRIF), INH and PYZ in plasma were assessed by HPLC analysis. Pharmacokinetic parameters namely AUC 0–24, AUC 0-inf, C max, T max, were calculated and subjected to different statistical tests ( Hauschke analysis, two way ANOVA, normal and log transformed confidence interval) at 90% confidence interval. In addition, elimination rate constant ( K el) and absorption efficiencies for each drug were also calculated. It was concluded that four drugs FDC tablet is bioequivalent for RIF, INH and PYZ to separate formulation at the same dose levels.