Evaluation of a one week intradermal regimen for rabies post-exposure prophylaxis: Results of a randomized, open label, active-controlled trial in healthy adult volunteers in India

ABSTRACT Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis. Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0–336 approximately 45%, from 47.69 h·μg/ml in period 1 to 26.33 h·μg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.)

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Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial

Journal of Infection and Chemotherapy ◽

10.1007/s10156-013-0622-9 ◽

2013 ◽

Vol 19 (4) ◽

pp. 740-749 ◽

Cited By ~ 18

Author(s):

Seizaburo Kashiwagi ◽

Akira Watanabe ◽

Hideyuki Ikematsu ◽

Shinichiro Awamura ◽

Takako Okamoto ◽

...

Keyword(s):

Controlled Trial ◽

Post Exposure Prophylaxis ◽

Double Blind ◽

Double Blind Placebo ◽

Post Exposure ◽

Household Contacts ◽

Exposure Prophylaxis

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Conjunctival tissue pharmacokinetic properties of topical azithromycin 1% and moxifloxacin 0.5% ophthalmic solutions: A single-dose, randomized, open-label, active-controlled trial in healthy adult volunteers

Clinical Therapeutics ◽

10.1016/j.clinthera.2008.10.020 ◽

2008 ◽

Vol 30 (11) ◽

pp. 2005-2014 ◽

Cited By ~ 11

Author(s):

Gail Torkildsen ◽

Terrence P. O'Brien

Keyword(s):

Single Dose ◽

Healthy Adult ◽

Controlled Trial ◽

Open Label ◽

Pharmacokinetic Properties ◽

Tissue Pharmacokinetic ◽

Adult Volunteers ◽

Ophthalmic Solutions

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Review: Insights on Current FDA-Approved Monoclonal Antibodies Against Ebola Virus Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.721328 ◽

2021 ◽

Vol 12 ◽

Author(s):

Olivier Tshiani Mbaya ◽

Philippe Mukumbayi ◽

Sabue Mulangu

Keyword(s):

Ebola Virus ◽

Virus Disease ◽

Controlled Trial ◽

Post Exposure Prophylaxis ◽

Post Exposure ◽

Robust Immune Response ◽

Critical Knowledge ◽

Republic Of The Congo ◽

Exposure Prophylaxis ◽

The Impact

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use.

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