PMID- 34190595
OWN - NLM
STAT- MEDLINE
DCOM- 20220103
LR  - 20240205
IS  - 2165-0497 (Electronic)
IS  - 2165-0497 (Linking)
VI  - 9
IP  - 1
DP  - 2021 Sep 3
TI  - A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous 
      Infusion in Rats and Dogs.
PG  - e0033921
LID - 10.1128/Spectrum.00339-21 [doi]
LID - 10.1128/spectrum.00339-21
AB  - The toxicity of tenofovir alafenamide (TAF) hemifumarate (HF) was evaluated when 
      administered by continuous subcutaneous (s.c.) infusion via an external infusion 
      pump for 28 days to rats and dogs. The toxicokinetics of TAF and two metabolites, 
      tenofovir (TFV) and tenofovir diphosphate (TFV-DP) were also evaluated. After 
      administration of TAF HF in rats and dogs, primary systemic findings supported an 
      inflammatory response that was considered minimal to mild. Gross pathology and 
      histopathologic evaluation of tissue surrounding the s.c. infusion site revealed 
      signs of inflammation, including edema, mass formation, fibrosis, and mononuclear 
      cell inflammation in groups receiving >/=300 mug/kg/day in rats and >/=25 mug/day in 
      dogs. Although these changes were observed in animals receiving vehicle, the 
      severity was greater in animals receiving TAF HF. Changes in the local tissue 
      were considered a TAF HF-mediated exacerbation of an inflammatory response to the 
      presence of the catheter. In rats, systemic and local findings were considered 
      not adverse due to their low severity and reversibility; therefore, the "no 
      observed adverse effect level" (NOAEL) was set at 1,000 mug/kg/day. Because none 
      of the systemic findings were related to systemic exposure to TAF, the systemic 
      NOAEL was set at 250 mug/kg/day in dogs. Due to the severity of the observations 
      noted, a NOAEL for local toxicity could not be established. Although these 
      results might allow for exploration of tolerability and pharmacokinetics of s.c. 
      administered TAF HF in humans, data suggest a local reaction may develop in 
      humans at doses below a clinically relevant dose. IMPORTANCE Human 
      immunodeficiency virus (HIV) infection continues to be a serious global human 
      health issue, with  approximately 38 million people living with HIV worldwide at the end of 
      2019. HIV preexposure prophylaxis (PrEP) has introduced the use of antiretroviral 
      therapies as another helpful tool for slowing the spread of HIV worldwide. One 
      possible solution to the problem of inconsistent access and poor adherence to HIV 
      PrEP therapies is the development of subcutaneous (s.c.) depots or s.c. 
      implantable devices that continuously administer protective levels of an HIV PrEP 
      therapy for weeks, months, or even years at a time. We evaluate here the toxicity 
      of tenofovir alafenamide, a potent inhibitor or HIV replication, after continuous 
      s.c. infusion in rats and dogs for HIV PrEP.
FAU - Zane, Doris
AU  - Zane D
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Roller, Shane
AU  - Roller S
AD  - Intarcia Therapeutics, Inc., Research Triangle Park, California, USA.
FAU - Shelton, Josephine
AU  - Shelton J
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Singh, Roshni
AU  - Singh R
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Jain, Rachna
AU  - Jain R
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Wang, Yan
AU  - Wang Y
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Yang, Bing
AU  - Yang B
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Felx, Melanie
AU  - Felx M
AD  - Charles River Laboratories, Senneville, Quebec, Canada.
FAU - Alessi, Thomas
AU  - Alessi T
AD  - Intarcia Therapeutics, Inc., Hayward, California, USA.
FAU - Feldman, Paul L
AU  - Feldman PL
AD  - Intarcia Therapeutics, Inc., Research Triangle Park, California, USA.
LA  - eng
GR  - INV-008912/GATES/Bill & Melinda Gates Foundation/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210630
PL  - United States
TA  - Microbiol Spectr
JT  - Microbiology spectrum
JID - 101634614
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Organophosphates)
RN  - 0 (tenofovir diphosphate)
RN  - 99YXE507IL (Tenofovir)
RN  - EL9943AG5J (tenofovir alafenamide)
RN  - JAC85A2161 (Adenine)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
MH  - Adenine/analogs & derivatives
MH  - Alanine/*toxicity
MH  - Animals
MH  - Anti-HIV Agents
MH  - Dogs
MH  - Edema
MH  - HIV Infections/drug therapy
MH  - HIV-1
MH  - Infusions, Subcutaneous/*methods
MH  - Male
MH  - Organophosphates
MH  - Pre-Exposure Prophylaxis
MH  - Rats
MH  - Tenofovir/*analogs & derivatives/therapeutic use/*toxicity
PMC - PMC8552772
OTO - NOTNLM
OT  - antiretroviral
OT  - human immunodeficiency virus
OT  - preexposure prophylaxis
OT  - subcutaneous
OT  - tenofovir alafenamide
EDAT- 2021/07/01 06:00
MHDA- 2022/01/04 06:00
PMCR- 2021/06/30
CRDT- 2021/06/30 12:16
PHST- 2021/07/01 06:00 [pubmed]
PHST- 2022/01/04 06:00 [medline]
PHST- 2021/06/30 12:16 [entrez]
PHST- 2021/06/30 00:00 [pmc-release]
AID - 00339-21 [pii]
AID - 10.1128/Spectrum.00339-21 [doi]
PST - ppublish
SO  - Microbiol Spectr. 2021 Sep 3;9(1):e0033921. doi: 10.1128/Spectrum.00339-21. Epub 
      2021 Jun 30.