title: Statistical evaluation of physiological variability of rifampicin in fixed dose combinations.
abstract: Tuberculosis is one of the microbial diseases having a long history of its occurrence and yet to be eradicated from the world. Due to the development of bacterial resistance, treatment has changed from monotherapy to combotherapy to fixed dose combinations (FDCs). Rifampicin has been found one of the most important anti-tubercular drugs, however variable bioavailability of rifampicin in some FDCs as well as separate formulations has been reported in the literature, and led to the development of WHO model protocol for evaluation of FDCs for bioequivalence trials. In present investigation, role of physiological variability in rifampicin bioequivalence was studied. Influence of subject's body weight, inter/intra-individual variability of elimination rate and impact of outliers on the decision of bioequivalence were investigated. Normalization of pharmacokinetic measures for bioequivalence (AUC and C(max)) were carried out as per body weights and elimination rate constants of subjects, then different statistical tests like two-way ANOVA, hauschke analysis, normal and log-transformed confidence interval were applied to check for the change in bioequivalence decision. It was found that normalization as per body weights did not play a significant role in the outcome of bioequivalence endpoint. Similarly, elimination rate variability and outliers have been found insignificant regarding final outcome of bioequivalence study. Hence, it has been concluded that physiological variability did not play a significant role in bioequivalence of rifampicin in FDCs.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India. panchagnula@yahoo.com
authors.forename: Ramesh
authors.initials: R
authors.lastname: Panchagnula
authors.forename: Jitendra
authors.initials: J
authors.lastname: Parmar
authors.forename: Kanwaljit
authors.initials: K
authors.lastname: Kaur
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Shantaram Ramdos
authors.initials: SR
authors.lastname: Bade
authors.forename: Yasvanth
authors.initials: Y
authors.lastname: Ashokraj
mesh_terms: D000704:Analysis of Variance; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002985:Clinical Protocols; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D017410:Practice Guidelines as Topic; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013810:Therapeutic Equivalency; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism; D014944:World Health Organization
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin