Phase I EnACT trial of the safety and tolerability of a novel oral formulation of amphotericin B

Caleb P. Skipper, Mucunguzi Atukunda, Anna Stadelman, Nicole W. Engen, Ananta S. Bangdiwala, Katherine H. Hullsiek, Mahsa Abassi, Joshua Rhein, Melanie R. Nicol, Eva Laker, Darlisha A. Williams, Raphael Mannino, Theresa Matkovits, David B. Meya, David R. Boulware

Research output: Contribution to journalArticlepeer-review

Abstract

Amphotericin B deoxycholate (AMB) has substantial toxicities. A novel encochleated amphotericin B deoxycholate (cAMB) formulation has oral bioavailability, efficacy in an animal model, and minimal toxicity due to targeted drug delivery into macrophages, where intracellular fungi reside. We conducted a phase I, ascending-dose trial of cAMB administered at 1.0 g, 1.5 g, or 2.0 g per day in 4 to 6 divided doses among HIV-positive survivors of cryptococcosis (n = 9 per cohort). We assessed the tolerability of cAMB and the adverse events (AEs) associated with cAMB treatment over 3 days. A second trial (n = 9) assessed the tolerability of 1.5 g/day given for 7 days. In the single-ascending-dose study, all subjects received their full daily dose without vomiting (100% tolerability). The cohort receiving 1.0 g had 4 transient clinical AEs in 2 subjects within 48 h and 8 laboratory AEs (n = 6 grade 2, n = 2 grade 1). The cohort receiving 1.5 g had 7 clinical AEs in 1 subject attributed to acute gastroenteritis (n = 4 grade 2) and 5 laboratory AEs (n = 1 grade 2). The cohort receiving 2.0 g had 20 clinical AEs among 5 subjects within 48 h (n = 3 grade 2) and 11 laboratory AEs (n = 2 grade 2, n = 1 grade 3). From a qualitative survey, 26 of 27 subjects (96%) preferred their experience with oral cAMB over their prior experience with intravenous (i.v.) AMB. The second, multiple-dose cohort received 1.5 g/ day for 1 week, with 98.4% (248/252) of the doses being taken. Overall, 5 clinical AEs (n = 5 grade 1) and 6 laboratory AEs (n = 6 grade 1) occurred without kidney toxicity. Oral cAMB was well tolerated when given in 4 to 6 divided daily doses without the toxicities commonly seen with i.v. AMB. (This study has been registered at ClinicalTrials.gov under registration no. NCT04031833.).

Original languageEnglish (US)
Article numbere00838
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number10
DOIs
StatePublished - Oct 2020

Bibliographical note

Funding Information:
This research was made possible through support from the National Institute of Neurological Disorders and Stroke (grant R01NS110519) and the Fogarty International Center (grant K01TW010268), including a combined grant via the Northern Pacific Global Health Fellows Program (grant D43TW009345), as well as the National Institute of Allergy and Infectious Diseases (grant T32AI055433).

Publisher Copyright:
Copyright © 2020 Skipper et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Amphotericin B
  • Antifungal agents
  • Cryptococcal meningitis
  • Cryptococcus
  • HIV
  • Human immunodeficiency virus
  • Pharmacokinetics

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