Anu Patel (1), Qianwen Wang (1), Natasha Strydom (1), Jacqueline Ernest (1), Eric Nuermberger (2), Véronique Dartois (3), Rada Savic (1)
(1) Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA, (2) Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, (3) Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA
Objectives: Tuberculosis (TB) is one of the world’s deadliest infectious diseases, causing 1.3 million deaths in 2022. Treatment success rates are 88% in individuals with drug-susceptible TB and 63% in those with drug-resistant forms of TB (DR-TB),1 revealing a gap for improvement. Current treatments include a combination of three drugs: bedaquiline (B), pretomanid (Pa), and linezolid (L) in individuals with DR-TB.2 While this regimen has demonstrated considerable efficacy in clinical trials, linezolid, a key component, caused adverse events, resulting in dose reductions and interruptions.3–6 Given this, there is interest in finding an alternative drug that can be utilized in TB regimens. Sutezolid and TBI-223 are newer oxazolidinones that have shown a safer profile than linezolid while maintaining efficacious activity in preclinical studies.7–9 These, along with linezolid, are being studied in the adaptive Phase 2a RAD-TB platform trial (NCT06192160), which aims to assess their efficacy in combination with BPa. Here, an integrated translational modeling approach, using preclinical and early clinical data to predict clinical efficacy and site-of-disease exposures, was applied for sutezolid and evaluated against previously modeled pharmacokinetic-pharmacodynamic (PK-PD) results of TBI-223 and linezolid to assess best-in-class.
Methods:
Data collection. Preclinical PK and PD data of sutezolid monotherapy and in combination with BPa were collected from BALB/c mice and New Zealand White (NZW) rabbits. PD was measured as bacterial colony-forming units (CFU) over time. Clinical PK data was utilized from a Phase 1 single ascending dose trial in healthy adults.10 Clinical CFU measurements were taken from a Phase 2a early bactericidal activity (EBA) trial for comparison to predictions.11
Preclinical modeling. A semi-mechanistic PK-PD model, incorporating a baseline model to account for bacterial dynamics with immune effect,12 was developed from BALB/c mice data to describe the combined baseline and drug effect on CFU decline. Mouse PK population estimates were fixed to drive PD, and direct and indirect relationships between plasma concentrations and drug effect at the site of disease (i.e., lungs) were tested. Site-of-disease PK models were developed using observations in NZW rabbits by linking plasma PK to tissue PK and estimating the rate and extent of partitioning from plasma to different tissue types.
Clinical simulations. Simulations of the Phase 2a clinical outcome (EBA, defined as CFU decline over 14 days of treatment) and Phase 2b outcomes (time to positivity and time to culture conversion) were performed for all oxazolidinones. As PK-PD relationships were assumed to be translatable across species, these clinical outcomes were simulated by fixing drug effect parameters derived from the mouse models and utilizing clinical PK parameters as the driver. A correction in drug exposure due to interspecies differences in plasma protein binding was applied. A similar approach for clinical site-of-disease simulations was employed, where clinical PK drove partitioning into tissue types. Partitioning extent estimated from rabbit models was corrected by a previously-derived interspecies relationship.
Results:
Preclinical PK-PD and site-of-disease PK models of sutezolid. The mouse PK model was best fit by a one-compartment model with linear absorption and elimination. All monotherapy PK-PD models were best described using a delayed Emax function. In the combination model (BPa + sutezolid), the best fit, which retained plausibility and parsimony, was parametrized as a shift in potency of sutezolid from monotherapy to combination. This shift was estimated before and after 28 days to show the difference in drug effect on fast- and slow-replicating bacteria.13Tissue data from 29 NZW rabbits, grouped into lung, cellular lesion, and caseum tissue types, were utilized in the site-of-disease models.
Clinical bactericidal activity and site-of-disease exposures of sutezolid. Data from 24 subjects were included in the clinical PK model to be used for simulations. The best-fitting model was a two-compartment model for sutezolid with nonlinear elimination into one compartment for its major metabolite. Relative bioavailability was estimated to be 0.6 for the highest dose of 1800 mg. Using PK-PD parameters from the chronic infection model, predicted EBA, quantified as the drop in log10CFU over 14 days of sutezolid monotherapy, closely aligned with observations (1.07 vs. 0.95).11 From monotherapy to combination, sutezolid potency (i.e., EC50) decreased by 94-99.95%. Sutezolid penetrated all tissue types, including caseum, the difficult-to-reach core of necrotizing lung granulomas. Caseum concentrations exceeded the relevant potency target (i.e., casMBC50 = 0.49) for 1 hour after dosing with sutezolid at a clinically-relevant dose of 1200 mg.
Comparison of sutezolid to TBI-223 and linezolid. For fairer analysis of oxazolidinone efficacy, the same dose (1200 mg daily) and infection model parameters were compared. Sutezolid was found to have the same Emax (0.999) but higher potency (0.02 vs. 2.87) than linezolid as monotherapy in the acute infection model. When in combination with BPa, sutezolid had a higher Emax (0.49 vs. 0.31) and higher potency (0.0003-0.004 vs. 0.20) than linezolid in the subacute infection model. TBI-223 had a lower Emax (0.44, 0.23) and lower potency (2.86, 0.16) than sutezolid in monotherapy and combination, respectively. When simulating time to culture conversion of each drug in combination with BPa in a virtual population of 1000 subjects, all individuals achieved culture conversion with sutezolid at 49 days after treatment, while 672 subjects remained unconverted at 56 days (censoring point) with TBI-223. Five subjects remained unconverted with linezolid at 56 days. Also, while sutezolid achieved some therapeutic exposure in caseum, TBI-223 and linezolid did not.
Conclusions: Preclinical-to-clinical translation of sutezolid exposure-response validated a previously developed tool14 and provided relevant predictions to inform current drug development. Direct comparisons of sutezolid to TBI-223 and linezolid simulations showed superior therapeutic potential of sutezolid in both bactericidal activity and in patients with lung lesions present. These results can later be compared to the observations of the RAD-TB trial to assess prediction accuracy and potentially provide insight into trial outcomes. Overall, this data-driven modeling approach provides a path for accelerated development of new treatments for TB, with utility in dose selection, rank-ordering of drug candidates, and regimen prioritization.
References:
[1] Global Tuberculosis Report 2023 2023.
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Reference: PAGE 32 (2024) Abstr 11121 [www.page-meeting.org/?abstract=11121]
Poster: Drug/Disease Modelling - Other Topics