Safety and tolerability of a novel oral formulation of amphotericin B: Phase I EnACT Trial

Background: Amphotericin B deoxycholate (AMB) has substantial toxicities. A novel encochleated amphotericin (cAMB) formulation has oral bioavailability, animal model efficacy, and minimal toxicity due to targeted drug delivery into macrophages where intracellular fungi reside.Methods: We conducted a phase I, ascending dose trial of cAMB administered at 1.0g, 1.5g, or 2.0g per day in 4-6 divided doses among HIV-positive survivors of cryptococcosis (n=9 per cohort). We assessed tolerability and adverse events (AE) over 3 days. A second trial (n=9) assessed tolerability of 1.5g/day given for 7 days.Results. In the single ascending dose study, all subjects received their full daily dose without vomiting (100% tolerability). The 1.0g cohort had 4 transient clinical AEs in 2 subjects within 48 hours, and 8 laboratory AEs (n=6 Grade 2; n=2 Grade 1). The 1.5g cohort had 7 clinical AEs in 1 subject attributed to acute gastroenteritis (n=4 Grade 2), and 5 laboratory AEs (n=1 Grade 2). The 2.0g cohort had 20 clinical AEs among 5 subjects within 48 hours (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 oral cAMB versus prior IV AMB experience. The second, multiple-dose cohort received 1.5g/day for one week with 98.4% (248/252) doses taken. Overall, 5 clinical AEs (n=5 Grade 1) and 6 laboratory AEs (n=6 Grade 1) occurred without kidney toxicity.Conclusions. Oral cAMB was well tolerated when given in 4-6 divided daily doses without the toxicities commonly seen with IV AMB.