title: Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients.
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 log(10) 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 log(10) 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 log(10) 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 C(max) 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.
authors.affiliation: Department of Biomedical Sciences, Stellenbosch University, Cape Town, South Africa. ahd@sun.ac.za
authors.forename: A H
authors.initials: AH
authors.lastname: Diacon
authors.forename: R
authors.initials: R
authors.lastname: Dawson
authors.forename: M
authors.initials: M
authors.lastname: Hanekom
authors.forename: K
authors.initials: K
authors.lastname: Narunsky
authors.forename: A
authors.initials: A
authors.lastname: Venter
authors.forename: N
authors.initials: N
authors.lastname: Hittel
authors.forename: L J
authors.initials: LJ
authors.lastname: Geiter
authors.forename: C D
authors.initials: CD
authors.lastname: Wells
authors.forename: A J
authors.initials: AJ
authors.lastname: Paccaly
authors.forename: P R
authors.initials: PR
authors.lastname: Donald
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles