Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of Amphotericin B

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 (<i>n</i> = 9 per cohort). We assessed the tolerability of cAMB and the adverse events (AEs) associated with cAMB treatment over 3 days. A second trial (<i>n</i> = 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 (<i>n</i> = 6 grade 2, <i>n</i> = 2 grade 1). The cohort receiving 1.5 g had 7 clinical AEs in 1 subject attributed to acute gastroenteritis (<i>n</i> = 4 grade 2) and 5 laboratory AEs (<i>n</i> = 1 grade 2). The cohort receiving 2.0 g had 20 clinical AEs among 5 subjects within 48 h (<i>n</i> = 3 grade 2) and 11 laboratory AEs (<i>n</i> = 2 grade 2, <i>n</i> = 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 (<i>n</i> = 5 grade 1) and 6 laboratory AEs (<i>n</i> = 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.).