One-Dose Efficacy of Long-Acting Sorfequiline in a Mouse Model of Tuberculosis Preventive Therapy
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Rationale
Tuberculosis preventive therapy (TPT) is essential for global tuberculosis control, yet estimated coverage remains well below global targets. Current World Health Organization (WHO)-recommended regimens require 1-9 months of treatment and are associated with suboptimal completion rates. Long-acting injectable (LAI) formulations offer the potential to improve TPT uptake and completion, with ideal products providing "one-and-done" options via a single administration. Sorfequiline, a second-generation diarylquinoline with superior potency over bedaquiline and lower QT prolongation risk, is a promising candidate for LAI TPT.
Objectives
To experimentally determine exposure-activity relationships for sorfequiline as TPT, estimate target plasma exposures, and characterize the pharmacokinetics (PK), tolerability, and efficacy of sorfequiline LAI formulations.
Methods
Oral sorfequiline dosing experiments established PK and pharmacodynamic relationships in a validated paucibacillary mouse model of TPT. Three candidate sorfequiline LAI formulations were evaluated for PK and tolerability in uninfected mice, followed by efficacy assessment compared to oral comparators (1HP, bedaquiline, sorfequiline).
Measurement and Main Results
Oral dosing experiments established a provisional target plasma C min of 35 ng/mL for bactericidal effect. All tested LAI formulations achieved this target for at least 4 weeks post-dose. In efficacy studies, all sorfequiline LAI regimens (62.5-250 mg/kg) and sorfequiline oral regimens demonstrated significantly greater bactericidal activity than 1HP and oral bedaquiline. Among mice receiving ≥125 mg/kg of any sorfequiline LAI, 92% were culture-negative at 12 weeks.
Conclusion
Superior efficacy of a single-dose sorfequiline LAI injection compared to 1HP indicates the potential to meet the WHO target product profile for an optimal "one-and-done" LAI TPT clinical regimen.
