Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients

Date
2011
Authors
Diacon A.H.
Dawson R.
Hanekom M.
Narunsky K.
Venter A.
Hittel N.
Geiter L.J.
Wells C.D.
Paccaly A.J.
Donald P.R.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
BACKGROUND: Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration. METHODS: Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 ± 9.9 kg; 30.7 ± 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log10 cfu/ml sputum/day. RESULTS: The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of ≥0.9 log10 cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 ± 0.056 log10 cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between Cmax and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity. CONCLUSIONS: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity. © 2011 The Union.
Description
Keywords
Delamanid, Early bactericidal activity, OPC-67683, Tuberculosis, delamanid, adult, article, bactericidal activity, clinical article, controlled study, dose response, drug absorption, drug blood level, drug dose comparison, drug efficacy, drug exposure, drug fatality, drug tolerability, female, human, lung tuberculosis, male, maximum plasma concentration, morning dosage, multicenter study, phase 2 clinical trial, priority journal, QT prolongation, randomized controlled trial, sputum smear
Citation
International Journal of Tuberculosis and Lung Disease
15
7
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