Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients
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.
Document Type: Regular Paper
Affiliations: 1: Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa 2: Centre for TB Research Innovation, University of Cape Town Lung Institute, Cape Town, South Africa 3: Otsuka Frankfurt Research Institute GmbH, Frankfurt am Main, Germany 4: Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland, USA 5: Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa
Publication date: 2011-07-01
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