Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Birkuš, Gabriel; Bam, Rujuta A.; Willkom, Madeleine; Frey, Christian; Tsai, Luke Y.; Stray, Kirsten M.; Yant, Stephen R.; Cihlář, Tomáš

doi:10.1128/aac.01834-15

Cited by 63 publications

(53 citation statements)

References 39 publications

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“…The intracellular metabolism of TAF has been studied intensively in PBMCs and macrophages, and the ester bond of TAF is known to be cleaved by lysosomal CatA (8,28,29). In primary human hepatocytes, CES1 is highly expressed, and in vitro combination results indicated that CES1 plays a major role in hydrolyzing TAF.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the enzymes involved in the activation of TAF in primary human hepatocytes, cells were incubated with TAF together with known cathepsin A inhibitors (approved hepatitis C virus [HCV] nonstructural 3 [NS3] protease inhibitors telaprevir and boceprevir), carboxylesterase 1 inhibitor (bis-p-nitrophenyl phosphate [BNPP]), CYP3A4, and P glycoprotein (P-gp) inhibitor (cobicistat), or the combination of telaprevir and BNPP (8,(22)(23)(24). Consistent with the result described above, incubation with 0.5 M TAF resulted in approximately 350 pmol/ one million cells of TFV-DP in the absence of any inhibitors (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…TDF is also widely used as the backbone of current anti-HIV combination regimens (6,7). For both HIV and HBV, the mechanism of action of TDF is intracellular metabolism to its pharmacologically active form, tenofovir diphosphate (TFV-DP), followed by competition with endogenous 2=-dATP for incorporation by the viral reverse transcriptase and subsequent chain termination of viral DNA replication (8,9). TFV-DP is an effective inhibitor of HBV reverse transcriptase, with an inhibitor constant (K i ) of 0.18 M in vitro (9).…”

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confidence: 99%

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Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Murakami

Wang

Park

et al. 2015

Antimicrob Agents Chemother

149

133

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Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment for HIV and hepatitis B virus (HBV) infections. Since the target tissue for HBV is the liver, the hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and in dogs in vivo were evaluated here. Incubation of primary human hepatocytes with TAF resulted in high levels of the pharmacologically active metabolite tenofovir diphosphate (TFV-DP), which persisted in the cell with a halflife of >24 h. In addition to passive permeability, studies of transfected cell lines suggest that the hepatic uptake of TAF is also facilitated by the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3, respectively). In order to inhibit HBV reverse transcriptase, TAF must be converted to the pharmacologically active form, TFV-DP. While cathepsin A is known to be the major enzyme hydrolyzing TAF in cells targeted by HIV, including lymphocytes and macrophages, TAF was primarily hydrolyzed by carboxylesterase 1 (CES1) in primary human hepatocytes, with cathepsin A making a small contribution. Following oral administration of TAF to dogs for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, higher liver TFV-DP levels were observed after administration of TAF than those given TDF. These results support the clinical testing of once-daily low-dose TAF for the treatment of HBV infection. Chronic hepatitis B (CHB) is a major global health problem, and the World Health Organization (WHO) estimates that ϳ240 million people worldwide are chronically infected by hepatitis B virus (HBV) (1) (http://www.who.int/mediacentre /factsheets/fs204/en/). The small-molecule anti-HBV agents currently approved by U.S. Food and Drug Administration (FDA) are all nucleoside/nucleotide analogs targeting HBV reverse transcriptase. Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is a current first-line treatment for CHB (2) and has demonstrated efficacy in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (3-5). TDF is also widely used as the backbone of current anti-HIV combination regimens (6, 7). For both HIV and HBV, the mechanism of action of TDF is intracellular metabolism to its pharmacologically active form, tenofovir diphosphate (TFV-DP), followed by competition with endogenous 2=-dATP for incorporation by the viral reverse transcriptase and subsequent chain termination of viral DNA replication (8, 9). TFV-DP is an effective inhibitor of HBV reverse transcriptase, with an inhibitor constant (K i ) of 0.18 M in vitro (9).A new prodrug of tenofovir, tenofovir alafenamide (TAF or GS-7340), was selected to more efficiently load HIV target cells while lowering circulating levels of TFV, resulting in reduced offtarget exposure (10-13). The administration of 25 mg of TAF in HIV-i...

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Murakami

Wang

Park

et al. 2015

Antimicrob Agents Chemother

149

133

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“…COBI is a more selective and potent mechanism-based cytochrome P450 3A (CYP3A) inhibitor than RTV, which enhances, or "boosts," the exposure of CYP3A substrates. 7,8 In vitro studies have shown that TAF is metabolized to TFV by cathepsin A in peripheral blood mononuclear cells and macrophages [9][10][11] and is also metabolized to TFV by carboxylesterase 1 in hepatocytes. As COBI has no antiretroviral activity, it can be used as a booster without concern that drug-resistant viruses may be selected, even in regimens that do not contain any protease inhibitors.…”

mentioning

confidence: 99%

Effects of a Nutritional Protein‐Rich Drink on the Pharmacokinetics of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide, and Tenofovir Compared With a Standard Meal in Healthy Japanese Male Subjects

Yamada

Ikushima

Nemoto

et al. 2017

Clinical Pharm in Drug Dev

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This study investigated the effects of ingested meal types on the pharmacokinetics of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), tenofovir alafenamide (TAF), and tenofovir (TFV) following a single administration of the single-tablet regimen (STR) of EVG/COBI/FTC/TAF (150/150/200/10 mg) in Japanese HIV-negative healthy subjects (n = 12). In this open-label, randomized, 3-way crossover study, the bioequivalence of the EVG/COBI/FTC/TAF STR following ingestion of a nutritional protein-rich drink with a reference treatment of taking a standard breakfast was evaluated. Administration under fasted conditions, no food intake, resulted in decreases in the mean AUC and C of EVG by 50% and 57%, respectively, relative to the administration with a standard breakfast, whereas the systemic exposure of EVG with a nutritional protein-rich drink was comparable to that with a standard breakfast. The mean AUC and C of COBI, FTC, TAF, and TFV were comparable regardless of meal intake or meal types. Although the package insert of the EVG/COBI/FTC/TAF STR states that the medication is recommended to be taken with food, this study provides an additional insight into HIV-1-infected patients that a light meal like a nutritional protein-rich drink can be an alternative to a standard meal.

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“…As metabolic abnormalities and drug–drug interactions are the critical side effects of PI-based regimens, it is essential that investigational PIs be screened for the known adverse effects prior to proceeding to clinical trials. Alternatively, the newly designed PIs can be developed as prodrugs [96,97] or nanoformulations [78,98] that can give better bioavailability profile with limited adverse effects.…”

Section: Strategies For Better Adverse Event Profiles Of Novel Pismentioning

confidence: 99%

Investigational protease inhibitors as antiretroviral therapies

Midde

Patters

Rao

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction Highly Active Antiretroviral Therapy (HAART) has tremendously improved the life expectancy of the HIV-infected population over the past three decades. Protease inhibitors have been one of the major classes of drugs in HAART regimens that are effective in treating HIV. However, the emergence of resistance and cross-resistance against protease inhibitors encourages researchers to develop new PIs with broad-spectrum activity, as well as novel means of enhancing the efficacy of existing PIs. Areas covered In this article we discuss recent advances in HIV protease inhibitor (PI) development, focusing on both investigational and experimental agents. We also include a section on pharmacokinetic booster drugs for improved bioavailability of protease inhibitors. Further, we discuss novel drug delivery systems using a variety of nanocarriers for the delivery of PIs across the blood-brain barrier to treat the HIV in the brain. Expert opinion We discuss our opinion on the promises and challenges on the development of novel investigational and experimental PIs that are less toxic and more effective in combating drug-resistance. Further, we discuss the future of novel nanocarriers that have been developed to deliver PIs to the brain cells. Although these are promising findings, many challenges need to be overcome prior to making them a viable option.

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Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors

Cited by 63 publications

References 39 publications

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Implications of Efficient Hepatic Delivery by Tenofovir Alafenamide (GS-7340) for Hepatitis B Virus Therapy

Effects of a Nutritional Protein‐Rich Drink on the Pharmacokinetics of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide, and Tenofovir Compared With a Standard Meal in Healthy Japanese Male Subjects

Investigational protease inhibitors as antiretroviral therapies

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