title: Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients.
abstract: OBJECTIVE
  SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days.
  
  
  METHODS
  Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection.
  
  
  RESULTS
  SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity.
  
  
  CONCLUSIONS
  SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.
authors: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Munich, Germany German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
authors: Norbert
authors: N
authors: Heinrich
authors: Division of Pulmonology, Department of Medicine, Groote Schuur Hospital and University of Cape Town Lung Institute, Cape Town, South Africa.
authors: Rodney
authors: R
authors: Dawson
authors: TASK Applied Science, Cape Town, South Africa.
authors: Jeannine
authors: J
authors: du Bois
authors: Division of Pulmonology, Department of Medicine, Groote Schuur Hospital and University of Cape Town Lung Institute, Cape Town, South Africa.
authors: Kim
authors: K
authors: Narunsky
authors: Sequella, Inc., Rockville, MD, USA.
authors: Gary
authors: G
authors: Horwith
authors: Sequella, Inc., Rockville, MD, USA.
authors: Andrew J
authors: AJ
authors: Phipps
authors: Sequella, Inc., Rockville, MD, USA.
authors: Carol A
authors: CA
authors: Nacy
authors: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands.
authors: Rob E
authors: RE
authors: Aarnoutse
authors: Radboud UMC/UCCZ Dekkerswald, Nijmegen, The Netherlands.
authors: Martin J
authors: MJ
authors: Boeree
authors: School of Medicine, University of St Andrews, St Andrews, UK.
authors: Stephen H
authors: SH
authors: Gillespie
authors: Medical Research Council Centre for Molecular and Cellular Biology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors: Amour
authors: A
authors: Venter
authors: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Munich, Germany German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
authors: Sonja
authors: S
authors: Henne
authors: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Munich, Germany German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
authors: Andrea
authors: A
authors: Rachow
authors: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors: Patrick P J
authors: PP
authors: Phillips
authors: Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Munich, Germany German Center for Infection Research (DZIF), Munich partner site, Munich, Germany hoelscher@lrz.uni-muenchen.de.
authors: Michael
authors: M
authors: Hoelscher
authors: TASK Applied Science, Cape Town, South Africa Medical Research Council Centre for Molecular and Cellular Biology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors: Andreas H
authors: AH
authors: Diacon
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005029:Ethylenediamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D000218:Adamantane; D012293:Rifampin
keywords: Phase 2; bactericidal activity; early bactericidal activity; pharmacokinetics; safety; treatment; tuberculosis