TY  - JOUR
AB  - INTRODUCTION: BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure-response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043. METHODS: A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium. RESULTS: In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%-65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043 + M2). CONCLUSIONS: We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.
AU  - Koele, S.E.*
AU  - Heinrich, N.*
AU  - De Jager, V.R.*
AU  - Dreisbach, J.*
AU  - Phillips, P.P.J.*
AU  - Gross-Demel, P.*
AU  - Dawson, R.*
AU  - Narunsky, K.*
AU  - Wildner, L.M.*
AU  - McHugh, T.D.*
AU  - Te Brake, L.H.M.*
AU  - Diacon, A.H.*
AU  - Aarnoutse, R.E.*
AU  - Hoelscher, M.
AU  - Svensson, E.M.*
C1  - 73797
C2  - 57231
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 1315-1323
TI  - Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043.
JO  - J. Antimicrob. Chemother.
VL  - 80
IS  - 5
PB  - Oxford Univ Press
PY  - 2025
SN  - 0305-7453
ER  - 

TY  - JOUR
AB  - 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.
AU  - Koele, S.E.*
AU  - Stoycheva, K.*
AU  - Mtweve, C.*
AU  - Manyama, C.*
AU  - Mpagama, S.*
AU  - Mhimbira, F.*
AU  - Wallis, R.*
AU  - Ntinginya, N.E.*
AU  - Liyoyo, A.*
AU  - Huglin, B.*
AU  - Minja, L.T.*
AU  - Wagnerberger, L.*
AU  - Zumba, T.*
AU  - Noreña, I.*
AU  - Peter, D.D.*
AU  - Beattie, T.*
AU  - Makkan, H.*
AU  - Sloan, D.J.*
AU  - Te Brake, L.H.M.*
AU  - Aarnoutse, R.E.*
AU  - McHugh, T.D.*
AU  - Wildner, L.*
AU  - Schildkraut, J.M.*
AU  - Aldana, B.H.*
AU  - Phillips, P.P.J.*
AU  - Hoelscher, M.
AU  - Svensson, E.M.*
AU  - Heinrich, N.*
C1  - 75069
C2  - 57787
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 2305-2313
TI  - 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.
JO  - J. Antimicrob. Chemother.
VL  - 80
IS  - 8
PB  - Oxford Univ Press
PY  - 2025
SN  - 0305-7453
ER  - 

TY  - JOUR
AB  - BACKGROUND: New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection. METHODS: Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months. RESULTS: B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens. CONCLUSIONS: BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.
AU  - Walter, K.*
AU  - Te Brake, L.H.M.*
AU  - Lemm, A.K.*
AU  - Hoelscher, M.
AU  - Svensson, E.M.*
AU  - Hölscher, C.*
AU  - Heinrich, N.*
C1  - 71433
C2  - 56172
CY  - Great Clarendon St, Oxford Ox2 6dp, England
SP  - 2607-2610
TI  - Investigating the treatment shortening potential of a combination of bedaquiline, delamanid and moxifloxacin with and without sutezolid, in a murine tuberculosis model with confirmed drug exposures.
JO  - J. Antimicrob. Chemother.
VL  - 79
IS  - 10
PB  - Oxford Univ Press
PY  - 2024
SN  - 0305-7453
ER  -