Tenofovir Disoproxil
(Synonyms: 替诺福韦酯; Bis(POC)-PMPA; GS 4331) 目录号 : GC37760
A prodrug of the antiviral tenofovir
Cas No.:201341-05-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Cells are plated into 48-well tissue culture plates (39,000 cells/mL) and allowed to grow for 48 h followed by treatment with vehicle or Tenofovir. Following the treatment period, cell viability is assessed using the MTT assay. The MTT assay relies on the conversion of tetrazolium dye 3-(4,5-dimethlthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan by NAD(P)H-dependent oxidoreductases. |
Animal experiment: | Twenty adult chronic WHV carrier woodchucks are stratified equally by age, sex, body weight, and serum GGT activity into five treatment groups consisting of four animals each: (i) Tenofovir Disoproxil Fumarate at 15.0 mg/kg once per day, (ii) Tenofovir Disoproxil Fumarate at 5.0 mg/kg/day, (iii) Tenofovir Disoproxil Fumarate at 1.5 mg/kg/day, (iv) Tenofovir Disoproxil Fumarate at 0.5 mg/kg/day, and (v) a placebo control. The woodchucks are treated daily for 4 weeks and observed for an additional 12 weeks following cessation of drug treatment. |
References: [1]. Murphy RA, et al. Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity. Int J Mol Sci. 2017 Mar 1;18(3) | |
Tenofovir disoproxil is a prodrug of the acyclic nucleoside phosphonate, tenofovir .1,2 Tenofovir is converted by cellular enzymes to tenofovir diphosphate, an obligate chain terminator that inhibits the activity of HIV reverse transcriptase and hepatitis B virus polymerase.3,4 Due to its rapid intracellular uptake, the anti-HIV activity of tenofovir disoproxil is reportedly >100-fold greater than that of the negatively charged tenofovir in a T cell line and primary blood lymphocytes.2
1.De Clercq, E.Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infectionsClin. Microbiol. Rev.16(4)569-596(2003) 2.Robbins, B.L., Srinivas, R.V., Kim, C., et al.Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPAAntimicrob. Agents Chemother.42(3)612-617(1998) 3.Balzarini, J., Vahlenkamp, T., Egberink, H., et al.Antiretroviral activities of acyclic nucleoside phosphonates [9-(2-phosphonylmethoxyethyl)adenine, 9-(2-phosphonylmethoxyethyl)guanine, (R)-9-(2-phosphonylmethoxypropyl)adenine, and MDL 74,968] in cell cultures and murine sarcoma virus-infected newborn NMRI miceAntimicrob. Agents Chemother.41(3)611-616(1997) 4.Balzarini, J., Holy, A., Jindrich, J., et al.Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: Potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurineAntimicrob. Agents Chemother.37(2)332-338(1993)
| Cas No. | 201341-05-1 | SDF | |
| 别名 | 替诺福韦酯; Bis(POC)-PMPA; GS 4331 | ||
| Canonical SMILES | O=C(OC(C)C)OCOP(OCOC(OC(C)C)=O)(CO[C@H](C)CN1C=NC2=C(N)N=CN=C12)=O | ||
| 分子式 | C19H30N5O10P | 分子量 | 519.44 |
| 溶解度 | DMSO: ≥ 38 mg/mL (73.16 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9252 mL | 9.6258 mL | 19.2515 mL |
| 5 mM | 0.385 mL | 1.9252 mL | 3.8503 mL |
| 10 mM | 0.1925 mL | 0.9626 mL | 1.9252 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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Emtricitabine and tenofovir alafenamide vs emtricitabine and Tenofovir Disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial
Lancet 2020 Jul 25;396(10246):239-254.PMID:32711800DOI:10.1016/S0140-6736(20)31065-5.
Background: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with Tenofovir Disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and Tenofovir Disoproxil fumarate for HIV prevention. Methods: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and Tenofovir Disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and Tenofovir Disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir Disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and Tenofovir Disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. Findings: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and Tenofovir Disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and Tenofovir Disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and Tenofovir Disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and Tenofovir Disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and Tenofovir Disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Interpretation: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and Tenofovir Disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and Tenofovir Disoproxil fumarate. Funding: Gilead Sciences.
Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or Tenofovir Disoproxil fumarate, and efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial
Lancet 2021 Apr 3;397(10281):1276-1292.PMID:33812487DOI:10.1016/S0140-6736(21)00314-7.
Background: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and Tenofovir Disoproxil fumarate; and efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate. Methods: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and Tenofovir Disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and Tenofovir Disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. Findings: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and Tenofovir Disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per μL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and Tenofovir Disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and Tenofovir Disoproxil fumarate group (three [2%] of 202; p=0·050). Interpretation: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and Tenofovir Disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. Funding: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.
Is Tenofovir Alafenamide Safer than Tenofovir Disoproxil Fumarate for the Kidneys?
AIDS Rev 2016 Oct-Dec;18(4):184-192.PMID:27438578doi
Tenofovir Disoproxil fumarate is currently the cornerstone of HIV treatment. Although it shows an overall good safety profile, numerous cases of nephrotoxicity have been reported. Tenofovir alafenamide is a novel tenofovir prodrug that has been developed to improve renal safety. Pharmacokinetic studies suggest a better renal tolerance of tenofovir alafenamide than Tenofovir Disoproxil fumarate, probably because tenofovir plasma concentrations are lower after tenofovir alafenamide administration. Consistently in clinical trials, renal tolerance seems to be improved in patients treated with tenofovir alafenamide. However, some questions remain. First, whether tenofovir can accumulate and lead to nephrotoxicity under specific circumstances after tenofovir alafenamide administration is unknown. Second, only "real-world practice" will inform us on the long-term renal safety of tenofovir alafenamide. Last, tenofovir alafenamide renal safety in patients with chronic kidney disease has not been studied in any randomized clinical trial. In conclusion, tenofovir alafenamide appears as a very promising drug and long-term safety will be an important determinant of its expanded use.
Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and Tenofovir Disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet HIV 2021 Jul;8(7):e397-e407.PMID:34197772DOI:10.1016/S2352-3018(21)00071-0.
Background: In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and Tenofovir Disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and Tenofovir Disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and Tenofovir Disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov, number NCT02842086. Findings: Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and Tenofovir Disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07-0·31]) and 15 in participants who had received emtricitabine and Tenofovir Disoproxil fumarate (0·30 infections per 100 person-years [0·17-0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and Tenofovir Disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23-1·26]). Approximately 78-82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and Tenofovir Disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p<0·0001). Interpretation: Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding: Gilead Sciences.
Is Tenofovir Disoproxil fumarate associated with weight loss?
AIDS 2021 Dec 15;35(Suppl 2):S189-S195.PMID:34848586DOI:10.1097/QAD.0000000000003083.
Background: Recent clinical trials have shown weight gain associated with newer antiretrovirals. It is unclear how the nucleoside reverse transcriptase inhibitor backbone affects weight. Recent evidence suggests greater weight gain with tenofovir alafenamide (TAF) compared with Tenofovir Disoproxil fumarate (TDF). However, it is not fully understood whether TDF contributes to weight suppression. Methods: A systematic search of PubMed, Embase and clinicaltrials.gov was conducted to identify all randomized control trials comparing TDF/FTC or TDF to control in HIV-negative individuals. The primary endpoint included the number of events of 5% weight loss. Mantel-Haenszel test with random-effects modelling was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Further analyses of gastrointestinal (GI) adverse events were also undertaken. Results: Seven PrEP trials: PARTNERS, VOICE, TDF-2, Bangkok PrEP, iPrEX, FEM-PrEP and HPTN 084 were included in the analysis of weight loss, with a total sample size of 19 359. One study (HPTN 084) compared TDF/FTC to cabotegravir (CAB). HIV-negative individuals taking TDF were more likely to experience weight loss compared with control [odds ratio (OR) 1.44; 95% CI 1.12-1.85; P = 0.005). Exposure to TDF was also linked to greater odds of vomiting (OR 1.81; 95% CI 1.20-2.73; P < 0.005). There were no increased odds of nausea, diarrhoea or loss of appetite. Conclusion: There is evidence in HIV-negative individuals that TDF may be associated with weight loss. Further research should be carried out in HIV-positive individuals, and clinical trials of TDF/FTC should publish weight data to widen the evidence base.