Norbert Heinrich1, Rodney Dawson2, Jeannine du Bois3, Kim Narunsky2, Gary Horwith4, Andrew J Phipps4, Carol A Nacy4, Rob E Aarnoutse5, Martin J Boeree6, Stephen H Gillespie7, Amour Venter8, Sonja Henne1, Andrea Rachow1, Patrick P J Phillips9, Michael Hoelscher10, Andreas H Diacon11. 1. 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. 2. Division of Pulmonology, Department of Medicine, Groote Schuur Hospital and University of Cape Town Lung Institute, Cape Town, South Africa. 3. TASK Applied Science, Cape Town, South Africa. 4. Sequella, Inc., Rockville, MD, USA. 5. Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands. 6. Radboud UMC/UCCZ Dekkerswald, Nijmegen, The Netherlands. 7. School of Medicine, University of St Andrews, St Andrews, UK. 8. Medical Research Council Centre for Molecular and Cellular Biology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 9. Medical Research Council Clinical Trials Unit at University College London, London, UK. 10. 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. 11. 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.
Abstract
OBJECTIVES: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. PATIENTS AND 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.
RCT Entities:
OBJECTIVES: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. PATIENTS AND METHODS: Smear-positive pulmonary TBpatients 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: Xavier A Kayigire; Sven O Friedrich; Lize van der Merwe; Andreas H Diacon Journal: Antimicrob Agents Chemother Date: 2017-03-24 Impact factor: 5.191
Authors: Marco Schito; Giovanni Battista Migliori; Helen A Fletcher; Ruth McNerney; Rosella Centis; Lia D'Ambrosio; Matthew Bates; Gibson Kibiki; Nathan Kapata; Tumena Corrah; Jamshed Bomanji; Cris Vilaplana; Daniel Johnson; Peter Mwaba; Markus Maeurer; Alimuddin Zumla Journal: Clin Infect Dis Date: 2015-10-15 Impact factor: 9.079
Authors: Lia D'Ambrosio; Rosella Centis; Giovanni Sotgiu; Emanuele Pontali; Antonio Spanevello; Giovanni Battista Migliori Journal: ERJ Open Res Date: 2015-05-06