Safety, Tolerability, Pharmacokinetics, and Metabolism of Telacebec (Q203) for the Treatment of Tuberculosis: a Randomized, Placebo-Controlled, Multiple Ascending Dose Phase 1B Trial.

A phase 1b, randomized, placebo-controlled, double-blind, multiple ascending dose study (NCT02858973) was conducted to assess the safety, tolerability, and pharmacokinetics of the new antituberculosis agent telacebec (Q203). A total of 47 healthy adult subjects entered the study; 36 received telacebec, and 11 received placebo. Telacebec at doses of 20, 50, 100, 160, 250, and 320 mg was orally administered once daily with a standard meal for 14 days. Multiple oral doses of telacebec up to 320 mg daily for 14 days appeared to be safe and well tolerated by healthy adult subjects in this study. There were no deaths, serious adverse events, or subject discontinuations due to adverse events. Following oral doses of telacebec, the overall extent (AUCτ) and peak (Cmax) exposures of telacebec increased from 538.94 to 10,098.47 ng·h/mL and from 76.43 to 1502.33 ng/mL, respectively, with increasing telacebec doses from 20 mg to 320 mg. A steady state was achieved for plasma telacebec by day 12, and there was 1.9- to 3.1-fold accumulation in the extent of telacebec exposure after daily doses for 14 days. Analysis of plasma samples from the participants indicated that telacebec was the primary circulating entity with no significant metabolites. Three potential metabolites of telacebec have been identified, which may be relatively minimal compared to the parent drug. Consistent with findings from preclinical and previous single-dose clinical studies, these results also support the potential of telacebec for further development as a safe and effective agent for the treatment of tuberculosis.

Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects.

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 to 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 to 800 mg), telacebec plasma concentration reached the maximal plasma concentration (Cmax) in average 2.0 to 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration versus time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for Cmax. Moderate delay in Tmax (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support further investigation of telacebec for the treatment of tuberculosis.

Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline.

RATIONALE: New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis. OBJECTIVES: To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B. METHODS: Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling. MEASUREMENTS AND MAIN RESULTS: Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe. CONCLUSIONS: B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).

Home-based administration of Sayana® Press: review and assessment of needs in low-resource settings.

A new presentation of the subcutaneous (SC) injectable contraceptive depot medroxyprogesterone acetate (DMPA) increases the possibilities for home and self-administration of this popular contraceptive method. Sayana® Press is DMPA-SC in the prefilled Uniject™ injection system and consists of one dose that provides 3 months of contraceptive protection. Studies indicate that lay caregiver and self-injection of various medications, including other injectable presentations of DMPA-SC, are acceptable and effective. Introduction of Sayana® Press in developing countries could extend injectable contraceptive delivery safely and effectively beyond the clinic and, eventually, into the home, allowing lay caregiver or self-administration. Research needs for low-resource settings include assessing the acceptability and feasibility of self-injection with Sayana® Press. Feasibility studies necessary for implementing a sustainable home-based delivery program include assessment of training, health systems, policies, infrastructure needs and programmatic considerations to optimize women's ability to manage their self-injection schedule.

Making evidence work for communities: the role of nongovernmental organizations in translating science to programs.

Evidence-informed public health refers to the process of applying proven interventions within the context of community preferences in order to achieve positive health impacts. A key role for nongovernmental organizations (NGOs) in evidence-informed public health is to use and expand on research to help shape appropriate interventions for diverse communities. This article suggests that NGOs are particularly well positioned for this role for a number of reasons, including their geographic reach, their engagement with diverse stakeholders, and their extragovernmental position, which enables them to develop and advocate for innovative, scientifically sound solutions to long-standing health challenges. Three case studies are presented that highlight how NGOs can harness these advantages to shape evidence-informed policies and programs to improve women's health: PATH's multicountry HPV Vaccines project, the International Consortium for Emergency Contraception, and a collaborative effort to combat maternal mortality in Mali.