Veronique de Jager (1), Laurynas Mockeliunas (2), Huifang You (2), Ulrika SH Simonsson (2), Tarryn Collings (1), Caryn Upton (1), Will Oosthuysen (1), Nikhil Gupte (3,4), Susan Dorman (5), Eric Nuermberger (3), Andreas Diacon (1), Kelly E. Dooley (6) and the COMRADE Study Team
(1) TASK, Cape Town, South Africa, (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (3) Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, (4) Johns Hopkins India, Pune, India, (5) Medical University of South Carolina, Charleston, South Carolina, USA, (6) Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Introduction/Objectives: Meropenem and rifampicin have been reported to have synergistic activity in vitro[1], indicating that co-administration of meropenem could decrease the minimum inhibitory concentration of rifampicin and overcome resistance in patients with rifampicin-resistant tuberculosis. The aim of this work was to evaluate the 14-day early bactericidal activity (EBA) of meropenem with and without rifampicin in colony forming units (CFU) and time to positivity (TTP) using a standardized pharmacometric model-based EBA analysis approach.
Methods: Participants with smear-positive rifampicin-resistant pulmonary tuberculosis from the COMRADE trial were included in this analysis (ClinicalTrials.gov Identifier: NCT03174184). Participants in arm A received meropenem (2 g as 0.53 hours intravenous infusion thrice daily) plus amoxicillin/clavulanic acid (500 mg/125 mg orally thrice daily) and rifampicin 20 mg/kg orally once daily. Participants in arm B received meropenem plus amoxicillin/clavulanic acid only. Blood samples for meropenem and rifampicin plasma pharmacokinetics (PK) were taken at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (12 and 24-hour post-dose samples were collected for rifampicin PK assessment only) on day 13. PK parameters were derived using non-compartmental analysis. Overnight sputum samples were collected at baseline and on days 1, 2, 3, 4, 6, 8, 10, 12 and 14 of treatment to determine CFU and TTP. CFU and TTP analyses were performed following a standardized pharmacometric model-based EBA analysis approach[2]. Sex, age, weight, BMI, ethnicity, HIV status, cavitary disease and extent of disease were evaluated on all model parameters, while the mean observed baseline bacterial load was evaluated on slope parameters using stepwise covariate modelling with adaptive scope reduction[3]. The area under the concentration-time curve from time 0 to last measured concentration (AUC0-last) and the maximum observed plasma concentration (cmax) of both meropenem and rifampicin were used as drug exposure drivers for bacterial killing in each of the biomarker models. Model selection and evaluation were based on objective function value (OFV), parameter uncertainties, visual predictive checks and other goodness-of-fit plots. Modelling was performed using NONMEM version 7.5.1 (ICON, Hanover, MD, USA)[4] through Perl-speaks-NONMEM (v. 5.3.0) and R statistical software (v. 4.2.2).
Results: In total, 623 CFU observations from 47 participants (29 participants from arm A and 18 participants from arm B) and 921 TTP observations from 50 patients (31 participants in arm A and 19 participants in arm B) were used for model building.
For CFU, the final model consisted of a mono-exponential function with inter-individual variability in baseline and CFU slope. CFU baseline was identified as a statistically significant covariate on CFU slope (p<0.01) where the CFU slope increased by 41% per 1 unit increase in baseline log10CFU/mL. No statistically significant exposure-response relationships were identified between the CFU slope and any of the PK parameters. Both treatment regimens showed a statistically significant EBA but no statistically significant difference in CFU slope was identified between the treatment arms.
For TTP, the final model consisted of a mono-exponential function, and inter-individual variability was included in both baseline and TTP slope. The presence of cavitary disease on chest X-ray on baseline was identified as a statistically significant covariate-parameter relationship (p<0.01) where participants with single or multiple cavities of diameter ≥ 4 cm in aggregate had 52% lower baseline (higher baseline bacterial load) compared to participants with no cavities or with the presence of single or multiple cavities with diameter < 4cm in aggregate. No statistically significant exposure-response relationships were identified between the TTP slope and any of the PK parameters. Both treatment arms showed statistically significant EBA but no statistically significant difference in TTP slope was identified between the treatment arms.
Conclusions: Previously developed standardized pharmacometric model-based EBA analysis approach was applied to analyse phase 2a trial data from the COMRADE trial. Meropenem with amoxicillin/clavulanate does not appear to restore rifampicin susceptibility for participants with rifampicin-resistant TB based on phase 2a data.
References:
[1] Kaushik A, Makkar N, Pandey P, Parrish N, Singh U, Lamichhane G. Carbapenems and Rifampicin Exhibit Synergy against Mycobacterium tuberculosis and Mycobacterium abscessus. Antimicrob Agents Chemother. 2015 Oct;59(10):6561-7. doi: 10.1128/AAC.01158-15. Epub 2015 Aug 10.
[2] Mockeliunas L, Faraj A, van Wijk RC, Upton CM, van den Hoogen G, Diacon AH, Simonsson USH. Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development. Front Pharmacol. 2023 Apr 13;14:1150243. doi: 10.3389/fphar.2023.1150243.
[3] Svensson RJ, Jonsson EN. Efficient and relevant stepwise covariate model building for pharmacometrics. CPT Pharmacometrics Syst Pharmacol. 2022 Sep;11(9):1210-1222. doi: 10.1002/psp4.12838. Epub 2022 Jul 19.
[4] Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ 1989-2011. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA
Reference: PAGE 32 (2024) Abstr 11061 [www.page-meeting.org/?abstract=11061]
Poster: Drug/Disease Modelling - Infection