Abstract

A PHARMACOVIGILANCE STUDY OF COMPARATIVE SAFETY ASSESSMENT OF BEDAQUILINE AND LEVOFLOXACIN, AMONG MULTI-DRUG RESISTANT TUBERCULOSIS PATIENTS IN GLOBAL MULTI-CENTRE TERTIARY CARE HOSPITALS, AND AN ANTITUBERCULAR MOLECULAR PHARMACOTHERAPEUTIC ANALYSIS OF BE

Dr. Moumita Hazra*

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Abstract

Introduction: Bedaquiline, a novel 1, 4 - diarylquinoline, inhibits mycobacterial adenosine triphosphate synthase, thereby inhibiting ATP generation, disrupting mycobacterial energy metabolism and replication of M. tuberculosis. Bedaquiline‟s initial bacteriostatic action is followed by a bactericidal effect after 5-7 days. Bedaquilinebased MDR-TB treatment regimens result in faster and more sustained disease resolution than bedaquiline-sparing MDR-TB treatment regimens. Levofloxacin, the S- or levorotatory isomer of racemic mixture of ofloxacin, is bactericidal to M. tuberculosis, MAC, M. fortuitum, and other atypical mycobacteria, with inhibitory effect on DNA gyrase, DNA topoisomerase IV and IL-1α, IL-6, IL-8. Objectives: The objective was to perform a pharmacovigilance study of comparative safety assessment of bedaquiline and levofloxacin, among multi-drug resistant tuberculosis patients in global multi-centre tertiary care hospitals, and an anti-tubercular molecular pharmacotherapeutic analysis of bedaquiline. Methods: A multi-centre, prospective, comparative, randomised and single-blinded study of 100 multi-drug resistant tuberculosis patients, and a molecular pharmacological analytical study, were performed. For 24 – 48 weeks, Group A patients were prescribed anti-tubercular drug oral bedaquiline 400 mg once daily followed for 2 weeks followed by 200 mg thrice weekly for 22 weeks, and Group B patients were prescribed oral levofloxacin 750 mg once daily, as part of MDR-TB treatment regimens. The comparative anti-tubercular safety assessment was done by the monitoring of adverse drug reactions, like nausea, headache, diarrhoea, insomnia, dizziness, constipation, ECG QT prolongation, arthralgia, myalgia, among Group A patients, and adverse drug reactions, like arthralgia, chest pain, nausea, vomiting, diarrhoea, dizziness, headache, haemoptysis, among Group B patients, with Adverse Event Case Report Forms, on days 0, 30, 60, 90, 120, 150, 180, 210, 240, 260, 300, 330, 360, and on further follow-ups. The patient compliance and molecular pharmacological analyses of bedaquiline, were also performed. Results: All the 100 patients completed the treatment thoroughly. There were no dropout patients due to adverse effects, none was lost to follow-up and none of the patients withdrew voluntarily. The safety assessment showed that both in Group A and Group B patients, the occurrence of adverse effects were statistically non-significant. The molecular pharmacological analysis of bedaquiline depicted its efficienacy in the pharmacotherapeutic application among global multi-drug resistant and extensively drug-resistant tuberculosis patients. Conclusions: The patients‟ adherence to anti-tubercular treatment was very high. Both bedaquiline and levofloxacin, were safe and tolerable among multi-drug resistant tuberculosis patients. The molecular pharmacological analysis of bedaquiline elaborated its exceptional efficacy.

Keywords: Pharmacovigilance, Diarylquinolines, Bedaquiline, Fluoroquinolones, Levofloxacin, Molecular Pharmacotherapeutics, Multi drug-resistant tuberculosis, Extensively drug-resistant tuberculosis.