58 research outputs found
Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations.
No full textTenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100-400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations
Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations
No full textBroad-spectrum Investigational Agent GS-5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Viral Infections with High Outbreak Potential
No full textAbstract
Background
Recent viral outbreaks with significant mortality such as Ebola virus (EBOV), SARS-coronavirus (CoV), and MERS-CoV reinforced the need for effective antiviral therapeutics to control future epidemics. GS-5734 is a novel nucleotide analog prodrug in the development for treatment of EBOV.
Method
Antiviral activity of GS-5734 has been established in vitro against a wide range of pathogenic RNA virus families, including filoviruses, coronaviruses, and paramyxoviruses (EC50 = 37 to 200 nM) (Warren et al., Nature 2016; Sheahan et al., Sci Transl Med 2017; Lo et al., Sci Rep 2017). Herein, we describe the in vivo translation of the broad-spectrum activity of GS-5734 in relevant animal disease models for Ebola, Marburg, MERS-CoV, and Nipah.
Result
Therapeutic efficacy against multiple filoviruses with 80–100% survival was observed in rhesus monkeys infected with lethal doses of EBOV (Kikwit/1995 or Makona/2014) or Marburg virus and treated with once daily intravenous (IV) administration of 5 to 10 mg/kg GS-5734 beginning 3 to 5 days post-infection (p.i.). In all rhesus monkey filovirus infection models, GS-5734 significantly reduced systemic viremia and ameliorated severe clinical disease signs and anatomic pathology. In mice infected with MERS-CoV, twice daily subcutaneous administration of 25 mg/kg GS-5734 beginning 1 day p.i. significantly reduced lung viral load and improved respiratory function. In rhesus monkeys, once-daily IV administration of 5 mg/kg GS-5734 initiated 1 day prior to MERS-CoV infection reduced lung viral load, improved clinical disease signs, and ameliorated severe lung pathology. Finally, in African green monkeys infected with a lethal dose of Nipah virus therapeutic once-daily IV administration of 10 mg/kg GS-5734, starting 1 day p.i. resulted in 100% survival to at least day 35 without any major respiratory or CNS symptoms.
Conclusion
GS-5734 is currently being tested in a phase 2 study in male Ebola survivors with persistent viral RNA in semen. Lyophilized drug formulation has been developed that can be administered to humans via a 30-minutes IV infusion and does not require cold chain storage. Together, these results support further development of GS-5734 as a broad-spectrum antiviral to treat viral infections with high mortality and significant outbreak potential.
Disclosures
R. Jordan, Gilead: Employee, Salary. J. Feng, Gilead: Employee, Salary
I. Trantcheva, Gilead: Employee, Salary. D. Babusis, Gilead: Employee, Salary. D. Porter-Poulin, Gilead: Employee, Salary. R. Bannister, Gilead: Employee, Salary
R. Mackman, Gilead: Employee, Salary. D. Siegel, Gilead: Employee, Salary
A. Ray, Gilead: Employee, Salary, T. Cihlar, Gilead: Employee, Salary.
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Clinical C<sub>max</sub> and observed CC<sub>50</sub> values for compounds evaluated in primary osteoblasts.
No full textClinical Cmax and observed CC50 values for compounds evaluated in primary osteoblasts.</p
GS-9219/VDC-1101 - a prodrug of the acyclic nucleotide PMEG has antitumor activity inspontaneous canine multiple myeloma
No full textIntracellular levels of TFV-DP in PBMCs for subjects receiving 25 mg TAF.
No full textIntracellular levels of TFV-DP in PBMCs for subjects receiving 25 mg TAF.</p
Intracellular TFV-DP levels detected in PBMC with a single 2-hour TAF pulse and washout.
No full textIntracellular TFV-DP levels detected in PBMC with a single 2-hour TAF pulse and washout.</p
Intracellular TFV-DP levels detected in primary osteoblasts with 3 days of 2-hour TAF pulses and washout.
No full textIntracellular TFV-DP levels detected in primary osteoblasts with 3 days of 2-hour TAF pulses and washout.</p
Intracellular TFV-DP levels detected in primary osteoblasts with a single 2-hour TAF pulse and washout.
No full textIntracellular TFV-DP levels detected in primary osteoblasts with a single 2-hour TAF pulse and washout.</p
Intracellular Nucleotide Levels during Coadministration of Tenofovir Disoproxil Fumarate and Didanosine in HIV-1-Infected Patients
No full textABSTRACT
Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2′-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10
6
cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10
6
cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.
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