Cardiac safety of bedaquiline, delamanid and moxifloxacin co-administered with or without varying doses of sutezolid or delpazolid for the treatment of drug-susceptible TB
Simon E Koele, Krista Stoycheva, Cyprian Mtweve, Christina Manyama, Stellah Mpagama, Francis Mhimbira, Robert Wallis, Nyanda Elias Ntinginya, Alphonce Liyoyo, Beno Huglin, Lilian Tina Minja, Larissa Wagnerberger, Tresphory Zumba, Ivan Noreña, Daud D Peter, Trevor Beattie, Heeran Makkan, Derek J Sloan, Lindsey Te Brake, Rob E Aarnoutse, Timothy D McHugh, Leticia Wildner, Jodie Schildkraut, Brian H Aldana, Patrick P J Phillips, Michael Hoelscher, Elin M Svensson, Norbert Heinrich, , Michael Hoelscher, Julia Dreisbach, Petra Gross-Demel, Larissa Hoffmann, Norbert Heinrich, Alia Razid, Wandini Lutchmun, Krista Stoycheva, Alexa Dierig, Anna Jarchow-MacDonald, Ivan Norena, Laura Paramo, Derek Sloan, Wilber Sabiiti, Stephen Gillespie, Lindsey te Brake, Elin Svensson, Chaima Mouhdad, Simon Koele, Rob Aarnoutse, Martin Boeree, Ralf Stemkens, Jodie Schildkraut, Anna Bateson, Robert Hunt, Timothy McHugh, Leticia Muraro Wildner, Priya Solanki, Patrick Phillips, Xue Gong, Brian Aldana, Angela Crook, Rodney Dawson, Kim Narunsky, Andreas Diacon, Veronique de Jager, Sven Friedrich, Ian Sanne, Mohammed Rassool, Gavin Churchyard, Modulakgotla Sebe, Heeran Makkan, Lucia Mokaba, Namhla Madikizela, John Mdluli, Jane Sithole, Robert Wallis, Trevor Beattie, Nyanda Elias Ntinginya, Chacha Mangu, Christina Manyama, Issa Sabi, Gabriel Rojas-Ponce, Bariki Mtafya, Lilian T Minja, Francis Mhimbira, Benno Mbeya, Tresphory Zumba, Mohamed Sasamalo, Klaus Reither, Levan Jugheli, Noel Sam, Gibson Kibiki, Hadija Semvua, Stellah Mpagama, Alphonce Liyoyo, Bayode Romeo Adegbite, Ayola Akim Adegnika, Martin Peter Grobusch, Martin P Grobusch, Bayode Romeo Adegbite, Bruce Kirenga, Celso Khosa, Isabel Timana, Mariott Nliwasa, Madalo MukokaAbstract
Introduction
Many drugs for the treatment of TB prolong the QTc interval, which is associated with an increased risk of developing a life-threatening arrhythmia known as torsades de pointes. Sutezolid and delpazolid are novel oxazolidinones with demonstrated bactericidal activity. We aimed to assess the effects of sutezolid or delpazolid co-administered with bedaquiline, delamanid and moxifloxacin on the QTcF interval (Fridericia’s correction). Furthermore, we developed a population pharmacodynamic model to assess the effects of drug exposure on the QTcTBT interval (TB-specific correction).
Methods
Participants were randomized to receive standard-dose bedaquiline, delamanid and moxifloxacin with varying doses of either sutezolid (no sutezolid, 600 mg daily, 1200 mg daily, 600 mg twice daily, 800 mg twice daily) or delpazolid (no delpazolid, 400 mg daily, 800 mg daily, 1200 mg daily, 800 mg twice daily). The QTc interval was determined using weekly ECG assessments.
Results
Data from 149 participants, yielding 2373 ECG observations were available for analysis. Nine participants (6.0%) experienced a Grade 3 QTcF prolongation as defined by the Common Terminology Criteria for Adverse Events v5.0. The population pharmacodynamic model predicted a 13.2 ms (95% CI: 10.9–15.3) increase of the QTcTBT in the first week of treatment, but no further increase after that. The exposure of bedaquiline’s M2 metabolite was found to drive part of the QTcTBT. No exposure–response relationship was identified for the other drugs investigated.
Conclusions
The drug regimens containing standard doses of bedaquiline, delamanid and moxifloxacin, and varying doses of sutezolid or delpazolid were not found to pose a high cardiac risk in a population without further QTc-relevant risk factors. However, close monitoring of the QTc interval remains essential in patients with TB treated with combination drug therapy with known QTc-prolonging drugs.