A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs
ABSTRACT 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-...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2021-09-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/Spectrum.00339-21 |
| _version_ | 1818941219359686656 |
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| author | Doris Zane Shane Roller Josephine Shelton Roshni Singh Rachna Jain Yan Wang Bing Yang Melanie Felx Thomas Alessi Paul L. Feldman |
| author_facet | Doris Zane Shane Roller Josephine Shelton Roshni Singh Rachna Jain Yan Wang Bing Yang Melanie Felx Thomas Alessi Paul L. Feldman |
| author_sort | Doris Zane |
| collection | DOAJ |
| description | ABSTRACT 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 μg/kg/day in rats and ≥25 μg/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 μg/kg/day. Because none of the systemic findings were related to systemic exposure to TAF, the systemic NOAEL was set at 250 μg/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 ∼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. |
| first_indexed | 2024-12-20T06:52:03Z |
| format | Article |
| id | doaj.art-ac5032bd3bee415591a2bda456ba4cb2 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-20T06:52:03Z |
| publishDate | 2021-09-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-ac5032bd3bee415591a2bda456ba4cb22022-12-21T19:49:31ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972021-09-019110.1128/Spectrum.00339-21A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and DogsDoris Zane0Shane Roller1Josephine Shelton2Roshni Singh3Rachna Jain4Yan Wang5Bing Yang6Melanie Felx7Thomas Alessi8Paul L. Feldman9Intarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Research Triangle Park, California, USAIntarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Hayward, California, USACharles River Laboratories, Senneville, Quebec, CanadaIntarcia Therapeutics, Inc., Hayward, California, USAIntarcia Therapeutics, Inc., Research Triangle Park, California, USAABSTRACT 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 μg/kg/day in rats and ≥25 μg/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 μg/kg/day. Because none of the systemic findings were related to systemic exposure to TAF, the systemic NOAEL was set at 250 μg/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 ∼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.https://journals.asm.org/doi/10.1128/Spectrum.00339-21tenofovir alafenamidesubcutaneoushuman immunodeficiency virusantiretroviralpreexposure prophylaxis |
| spellingShingle | Doris Zane Shane Roller Josephine Shelton Roshni Singh Rachna Jain Yan Wang Bing Yang Melanie Felx Thomas Alessi Paul L. Feldman A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs Microbiology Spectrum tenofovir alafenamide subcutaneous human immunodeficiency virus antiretroviral preexposure prophylaxis |
| title | A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs |
| title_full | A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs |
| title_fullStr | A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs |
| title_full_unstemmed | A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs |
| title_short | A 28-Day Toxicity Study of Tenofovir Alafenamide Hemifumarate by Subcutaneous Infusion in Rats and Dogs |
| title_sort | 28 day toxicity study of tenofovir alafenamide hemifumarate by subcutaneous infusion in rats and dogs |
| topic | tenofovir alafenamide subcutaneous human immunodeficiency virus antiretroviral preexposure prophylaxis |
| url | https://journals.asm.org/doi/10.1128/Spectrum.00339-21 |
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