Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Jul 10;17(7):e0011392.
doi: 10.1371/journal.pntd.0011392. eCollection 2023 Jul.

A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity

Negar Alami  1   2 , David C Carter  1   3 , Nisha V Kwatra  1   4 , Weihan Zhao  1 , Linda Snodgrass  1 , Ariel R Porcalla  1 , Cheri E Klein  1 , Daniel E Cohen  1 , Loretta Gallenberg  1   3 , Melina Neenan  1 , Robert A Carr  1   3 , Kennan C Marsh  1 , Dale J Kempf  1   3
Affiliations
Clinical Trial

A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity

Negar Alami et al. PLoS Negl Trop Dis. .

Abstract

Background: The parasitic filariae responsible for onchocerciasis and lymphatic filariasis are host to an endosymbiotic bacterium, Wolbachia, which is essential to the fertility and development of the parasites. We performed a Phase-I pharmacokinetic, safety and food-effect study on single and multiple ascending doses of flubentylosin (ABBV-4083), a macrolide antibacterial with activity against Wolbachia, intended to sterilize and eliminate the parasites.

Methods: Seventy-eight healthy adults were exposed to flubentylosin; 36 were exposed to single ascending 40, 100, 200, 400 or 1000 mg doses; 12 received 1000 mg in the food-effect part; and 30 received multiple ascending daily doses of 100 mg for 7 days, 200 mg for 7 or 14 days, or 400 mg for 7 or 14 days. Twenty-two subjects received placebo.

Results: Maximum concentrations (Cmax) of flubentylosin were reached after 1-2 hours, with a half-life < 4 hours at doses ≤ 400 mg. Cmax and AUC increased in a more than dose-proportional manner, with similar exposure after multiple dose administration. The most frequently reported adverse events were nausea (8/78, 10%) and headache (6/78, 8%). Two subjects given a single dose of flubentylosin 1000 mg in the food-effect part experienced reversible asymptomatic ALT and AST elevations at Grade 2 or Grade 4, with no elevation in bilirubin, deemed related to study drug. The effect of food on exposure parameters was minimal. No treatment-related serious adverse events were reported.

Discussion: Flubentylosin 400 mg for 14 days was the maximum tolerated dose in this first-in-human, Phase-I study in healthy adults. Based on preclinical pharmacokinetic/pharmacodynamic modeling, flubentylosin 400 mg once daily for 7 or 14 days is expected to be an effective dose. A Phase-II, proof-of-concept study with flubentylosin using these regimens is currently ongoing in patients with onchocerciasis in Africa.

PubMed Disclaimer

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors are or were employees of AbbVie during the work of this study and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication. DJK, LG and RAC are retirees of AbbVie. NVK is currently an employee of the Food and Drug Administration. NNA is currently an employee of Pfizer.

Figures

Fig 1
Fig 1. Patient Disposition in Phase-I Study on Flubentylosin.
Fig 2
Fig 2. Mean Blood Flubentylosin Concentrations Versus Time Profiles after Single Oral Administration of Ascending Doses from 40 mg to 1000 mg (Part 1), Linear (top) and Log-linear (bottom) Scales.
Fig 3
Fig 3. Mean Dose-normalized Cmax and AUC of Flubentylosin after Single Oral Administration of Ascending Doses from 40 mg to 1000 mg (Part 1).
Fig 4
Fig 4. Mean Blood Flubentylosin Concentrations versus Time Profiles after Administration of Flubentylosin 1000 mg under Fasting and Fed Conditions in Part 2 (Food Effect), Linear (top) and Log-linear (bottom) Scales.
Fig 5
Fig 5. Mean Blood Flubentylosin Concentrations versus Time Profiles after Administration of Multiple Ascending Doses of Flubentylosin in Part 3 (Upper Panels Linear Scale—Lower Panels Log-Linear Scale)
See this image and copyright information in PMC

References

    1. James SL, Abate D, Abate KH et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study. Lancet. 2017;392,10159:1789–1858. - PMC - PubMed
    1. Saint André Av, Blackwell NM, Hall LR, et al. The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science. 2002;295(5561):1892–5. doi: 10.1126/science.1068732 . - DOI - PubMed
    1. Magill AJ, Hill DR, Solomon T, Ryan ET. Hunter’s Tropical Medicine and Emerging Infectious Diseases. Ninth edition. Edinburgh: Elsevier; 2012.
    1. Molyneux DH, Hopkins AD, Bradley MH, Kelly-Hope LA. Multidimensional complexities of filariasis control in an era of large-scale mass drug administration programmes: A can of worms. Parasit. Vectors 2014;7:363. doi: 10.1186/1756-3305-7-363 - DOI - PMC - PubMed
    1. Taylor M, Hoerauf A, Bockarie M. Lymphatic filariasis and onchocerciasis. Lancet 2010;376:1175–1185. doi: 10.1016/S0140-6736(10)60586-7 . - DOI - PubMed

Publication types