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 (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.).

Keywords: Cryptococcus; HIV; amphotericin B; antifungal agents; cryptococcal meningitis; human immunodeficiency virus; pharmacokinetics.

Copyright © 2020 Skipper et al.

Figures

FIG 1

Illustration of cochleate technology. Amphotericin B is embedded within the phosphatidylserine bilayers of the cochleate, along with calcium ions. The cochleate protects the cAMB from digestive processes in the gastrointestinal tract until absorbed. Once absorbed, the cochleate is phagocytosed by macrophages. Due to the higher calcium concentration in the cochleate than in the cytoplasm of the macrophage, the cochleate is pulled open as calcium ions rush out, allowing intracellular delivery of the amphotericin B.

FIG 2

Pharmacokinetic data from the EnACT (encochleated oral amphotericin for cryptococcal meningitis) phase IA study. The median AUCs from time zero to the last quantifiable concentration in the plasma of the cohorts receiving doses of 1.0 g, 1.5 g, and 2.0 g were 1,970 ng · h/ml (IQR, 1,660 to 2,480 ng · h/ml), 2,660 ng · h/ml (IQR, 1,940 to 2,910 ng · h/ml), and 2,180 ng · h/ml (IQR, 1,790 to 2,630 ng · h/ml), respectively. The median cAMB plasma concentrations at various time points are visually displayed in the line graph. No statistically significant differences in Cmax or AUC were found between groups. Error bars represent the interquartile range for each cohort. The P values were calculated by the Kruskal-Wallis ANOVA. Abbreviations: AUC0-48, area under the curve from 0 to 48 h; Cmax, maximum concentration in plasma.