PMID- 32747357
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20210617
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 64
IP  - 10
DP  - 2020 Sep 21
TI  - Phase I EnACT Trial of the Safety and Tolerability of a Novel Oral Formulation of 
      Amphotericin B.
LID - 10.1128/AAC.00838-20 [doi]
LID - e00838-20
AB  - 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.).
CI  - Copyright (c) 2020 Skipper et al.
FAU - Skipper, Caleb P
AU  - Skipper CP
AUID- ORCID: 0000-0002-0000-8876
AD  - Infectious Diseases Institute, Makerere University, Kampala, Uganda 
      skipp015@umn.edu.
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Atukunda, Mucunguzi
AU  - Atukunda M
AD  - Infectious Diseases Institute, Makerere University, Kampala, Uganda.
FAU - Stadelman, Anna
AU  - Stadelman A
AD  - Infectious Diseases Institute, Makerere University, Kampala, Uganda.
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Engen, Nicole W
AU  - Engen NW
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Bangdiwala, Ananta S
AU  - Bangdiwala AS
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Hullsiek, Katherine H
AU  - Hullsiek KH
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Abassi, Mahsa
AU  - Abassi M
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Rhein, Joshua
AU  - Rhein J
AUID- ORCID: 0000-0002-0480-9646
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Nicol, Melanie R
AU  - Nicol MR
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Laker, Eva
AU  - Laker E
AD  - Infectious Diseases Institute, Makerere University, Kampala, Uganda.
FAU - Williams, Darlisha A
AU  - Williams DA
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
FAU - Mannino, Raphael
AU  - Mannino R
AD  - Matinas Biopharma, Bedminster, New Jersey, USA.
FAU - Matkovits, Theresa
AU  - Matkovits T
AD  - Matinas Biopharma, Bedminster, New Jersey, USA.
FAU - Meya, David B
AU  - Meya DB
AD  - Infectious Diseases Institute, Makerere University, Kampala, Uganda.
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
AD  - College of Health Sciences, Makerere University, Kampala, Uganda.
FAU - Boulware, David R
AU  - Boulware DR
AUID- ORCID: 0000-0002-4715-0060
AD  - University of Minnesota, Minneapolis, Minnesota, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT04031833
GR  - R01 NS110519/NS/NINDS NIH HHS/United States
GR  - UL1 TR002494/TR/NCATS NIH HHS/United States
GR  - K01 TW010268/TW/FIC NIH HHS/United States
GR  - T32 AI055433/AI/NIAID NIH HHS/United States
GR  - D43 TW009345/TW/FIC NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200921
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antifungal Agents)
RN  - 7XU7A7DROE (Amphotericin B)
SB  - IM
MH  - *Amphotericin B/adverse effects
MH  - Animals
MH  - Antifungal Agents/adverse effects
MH  - *Cryptococcosis/drug therapy
MH  - Fungi
PMC - PMC7508607
OTO - NOTNLM
OT  - Cryptococcus
OT  - HIV
OT  - amphotericin B
OT  - antifungal agents
OT  - cryptococcal meningitis
OT  - human immunodeficiency virus
OT  - pharmacokinetics
EDAT- 2020/08/05 06:00
MHDA- 2021/06/22 06:00
PMCR- 2020/09/21
CRDT- 2020/08/05 06:00
PHST- 2020/05/01 00:00 [received]
PHST- 2020/07/24 00:00 [accepted]
PHST- 2020/08/05 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/08/05 06:00 [entrez]
PHST- 2020/09/21 00:00 [pmc-release]
AID - AAC.00838-20 [pii]
AID - 00838-20 [pii]
AID - 10.1128/AAC.00838-20 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00838-20. doi: 
      10.1128/AAC.00838-20. Print 2020 Sep 21.