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Safety, pharmacokinetics, relative bioavailability and dose linearity of four formulations of emodepside in healthy male subjects
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  • Jean-Yves Gillon,
  • Jeremy Dennison,
  • Frans Van Den Berg,
  • Sophie Delhomme,
  • Karen Dequatre-Cheeseman,
  • Claudia Peña-Rossi,
  • Natalie Strub-Wourgaft,
  • Sabine Specht,
  • Belen Pedrique,
  • Frederic Monnot,
  • Susanne Skrabs,
  • Maria-Luisa Rodriguez,
  • Heino Stass
Jean-Yves Gillon
Drugs for Neglected Diseases initiative
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Jeremy Dennison
Hammersmith Medicines Research Ltd
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Frans Van Den Berg
Hammersmith Medicines Research Ltd
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Sophie Delhomme
Drugs for Neglected Diseases initiative
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Karen Dequatre-Cheeseman
Drugs for Neglected Diseases initiative
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Claudia Peña-Rossi
Drugs for Neglected Diseases initiative
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Natalie Strub-Wourgaft
Drugs for Neglected Diseases initiative
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Sabine Specht
Drugs for Neglected Diseases initiative
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Belen Pedrique
Drugs for Neglected Diseases initiative
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Frederic Monnot
Drugs for Neglected Diseases initiative
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Susanne Skrabs
Bayer AG
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Maria-Luisa Rodriguez
Bayer AG
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Heino Stass
Bayer AG
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Abstract

Aims: Emodepside is an anthelmintic, originally developed for veterinary use. We investigated the safety, pharmacokinetics, relative bioavailability and dose linearity of four oral formulations of emodepside in healthy male subjects. Methods: Three randomised, parallel‐group, controlled, Phase I studies were conducted using various oral formulations, involving 79 subjects in ten cohorts in the single-ascending-dose study, 24 subjects in three ascending-dose cohorts in the multiple-ascending-dose study and 77 subjects in seven different cohorts in the relative bioavailability study. Pharmacokinetics and safety assessments were performed up to 21, 30 and 7 days, respectively. Results: As a liquid service formulation, emodepside was rapidly absorbed under fasting conditions, with dose-proportional increases in plasma concentrations at doses from 1 mg to 40 mg. The half-life during the first 24 hours after dosing was around 11 hours, followed by a terminal elimination half-life > 500 hours. Emodepside was less bioavailable in the fed state. The rate of absorption was slower and Cmax was lower with the amorphous solid dispersion tablets compared to the liquid service formulation. Emodepside was well tolerated overall with no major safety concerns. Conclusion: These Phase I studies with various dosage forms revealed a pharmacokinetic profile suggesting good tissue distribution of emodepside and a long terminal half‐life. A 15 mg dose with the gastrosoluble tablet is predicted to provide exposure that will achieve the target concentration for clinical efficacy. These data enabled us to select a field-adapted tablet formulation that will open the way for further clinical development of emodepside in individuals with onchocerchiasis.

Peer review status:UNDER REVIEW

26 Aug 2020Submitted to British Journal of Clinical Pharmacology
27 Aug 2020Assigned to Editor
27 Aug 2020Submission Checks Completed
06 Sep 2020Reviewer(s) Assigned