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- Title
A Phase-I pharmacokinetic, safety and food-effect study on flubentylosin, a novel analog of Tylosin-A having potent anti-Wolbachia and antifilarial activity.
- Authors
Alami, Negar; Carter, David C.; Kwatra, Nisha V.; Zhao, Weihan; Snodgrass, Linda; Porcalla, Ariel R.; Klein, Cheri E.; Cohen, Daniel E.; Gallenberg, Loretta; Neenan, Melina; Carr, Robert A.; Marsh, Kennan C.; Kempf, Dale J.
- 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. Author summary: Onchocerciasis and lymphatic filariasis are neglected tropical diseases caused by parasitic filarial nematodes. Current efforts to eliminate these diseases are hindered by a lack of drugs that permanently sterilize and/or kill the adult worms. Antibacterials, including doxycycline, have been shown to deplete Wolbachia, an endosymbiotic bacterium essential to the fertility and development of the adult worms, leading to their permanent sterilization and death. However, doxycycline is contraindicated in women of child-bearing age, breastfeeding women, and children, and must be given for 4–6 weeks to be effective. There is a need for agents with fewer contraindications and a shorter treatment regimen. Flubentylosin is an antibacterial with demonstrated anti-Wolbachia activity in several animal models of filarial disease. The present first-in-human Phase-I clinical study investigated the safety and pharmacokinetics of flubentylosin in healthy male and female subjects after single and multiple ascending doses, as well as the effect of food on the pharmacokinetics of flubentylosin, in order to identify appropriate regimens for Phase-II studies. Treatment regimens with 400 mg flubentylosin for 7 or 14 days were selected for further investigation.
- Subjects
AFRICA; PARASITIC diseases; PHARMACOKINETICS; ONCHOCERCIASIS; ADVERSE health care events; FILARIASIS
- Publication
PLoS Neglected Tropical Diseases, 2023, Vol 17, Issue 7, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0011392