Stability behaviour of antiretroviral drugs and their combinations. 4: Characterization of degradation products of tenofovir alafenamide fumarate and comparison of its degradation and stability behaviour with tenofovir disoproxil fumarate

Golla, Vijaya Madhyanapu; Kurmi, Moolchand; Shaik, Karimullah; Singh, Saranjit

doi:10.1016/j.jpba.2016.08.022

Cited by 47 publications

(27 citation statements)

References 18 publications

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“…S1 in the supplemental material) using the shake flask method. We observed low rates of TAF degradation (27) in phosphate-buffered saline (PBS) in in vitro release testing medium (half-life of 2.8 days at pH 7.4 at 37°C in PBS) as well as in the implant (see Supplemental 1 and 2 in the supplemental material file), although until the end of the release curve, we observed that Ͼ90% of the internal contents were in the parent form. Molar amounts of TAF and its main TAF-related substances [(R)-9-(2-phosphonomethoxypropyl)adenine (PMPA) monoamidate and tenofovir] were calculated and con- verted to a mass of TAF depleted from the core.…”

Section: Resultsmentioning

confidence: 87%

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Simpson

Sung

et al. 2020

Antimicrob Agents Chemother

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We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

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Section: Resultsmentioning

confidence: 87%

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Simpson

Sung

et al. 2020

Antimicrob Agents Chemother

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“…Drug release from implants was evaluated in vitro ( Figure 2 ) using the shake flask method. We observed slow rates of TAF degradation (27) in phosphate-buffered saline (PBS) in in vitro release testing media (half-life of ∼48 hours at pH 7.4 at 37 °C in PBS), as well as in the implant (see Suppl. 1 ).…”

Section: Resultsmentioning

confidence: 99%

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Simpson²,

Sung³

et al. 2019

Preprint

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We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbits and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a dose of 10 µg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. Inflammation in the primates was markedly lower in the placebo group than the active implant. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve sustained target dose we observed unacceptable inflammatory response locally at the implant tissue interface.

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“…The IVRs are comprised of different polyurethane polymers, release different active drugs [TDF and TFV], contain different excipients, and exhibit different release profiles. Unlike TFV, TDF is a prodrug that is hydrolyzed primarily within cells but may also be hydrolyzed when it comes in contact with CVF, releasing fumarate/fumaric acid and potential degradation products such as formaldehyde [ 61 , 62 ]. While one possible hypothesis for the cause of the grade 1 genital ulcers seen in the phase I TDF IVR study is the effect of sustained TFV-DP concentrations, another plausible hypothesis is that the epithelial lesions are related to TDF degradation products, alone or synergized by semen or mechanical effects of sex.…”

Section: Discussionmentioning

confidence: 99%

Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women

et al. 2018

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To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94–100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing.Trial registration ClinicalTrials.gov #NCT02235662

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Stability behaviour of antiretroviral drugs and their combinations. 4: Characterization of degradation products of tenofovir alafenamide fumarate and comparison of its degradation and stability behaviour with tenofovir disoproxil fumarate

Cited by 47 publications

References 18 publications

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women

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