Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque
| Autor: | Mary E. Moreno, Michael Murphey-Corb, Stefan G. Sarafianos, Jose M. Rivera, Barbara Sloan, Cheryl A. Stoddart, Galina Kosikova, Pheroze Joshi, Michael A. Parniak, Sofiya A. Galkina, Aaron B. Reeve |
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| Rok vydání: | 2015 |
| Předmět: |
HIV Infections
Mice SCID Pharmacology medicine.disease_cause Monocytes Mice Oral administration Pharmacology (medical) Viral Simian immunodeficiency virus Pharmacology and Pharmaceutical Sciences Flow Cytometry Farnesol Infectious Diseases Blood-Brain Barrier 5.1 Pharmaceuticals Medical Microbiology 6.1 Pharmaceuticals RNA Viral Reverse Transcriptase Inhibitors HIV/AIDS Simian Immunodeficiency Virus Development of treatments and therapeutic interventions Infection Half-Life Anti-HIV Agents Viremia In Vitro Techniques Biology SCID Antiviral Agents Microbiology Peripheral blood mononuclear cell Pharmacokinetics medicine Animals Humans Potency Evaluation of treatments and therapeutic interventions Diazonium Compounds medicine.disease Macaca mulatta Virology Reverse transcriptase HIV-1 RNA Nucleoside |
| Zdroj: | Antimicrobial agents and chemotherapy, vol 59, iss 7 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.05036-14 |
| Popis: | Like normal cellular nucleosides, the nucleoside reverse transcriptase (RT) inhibitor (NRTI) 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) has a 3′-hydroxyl moiety, and yet EFdA is a highly potent inhibitor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication with activity against a broad range of clinically important drug-resistant HIV isolates. We evaluated the anti-HIV activity of EFdA in primary human cells and in HIV-infected humanized mice. EFdA exhibited excellent potency against HIV JR-CSF in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs), with a 50% inhibitory concentration of 0.25 nM and a selectivity index of 184,000; similar antiviral potency was found against 12 different HIV clinical isolates from multiple clades (A, B, C, D, and CRF01_AE). EFdA was readily absorbed after oral dosing (5 mg/kg of body weight) in both mice and the rhesus macaque, with micromolar levels of the maximum concentration of drug in serum ( C max ) attained at 30 min and 90 min, respectively. Trough levels were at or above 90% inhibitory concentration (IC 90 ) levels in the macaque at 24 h, suggesting once-daily dosing. EFdA showed reasonable penetration of the blood-brain barrier in the rhesus macaque, with cerebrospinal fluid levels at approximately 25% of plasma levels 8 h after single oral dosing. Rhesus PBMCs isolated 24 h following a single oral dose of 5 mg/kg EFdA were refractory to SIV infection due to sufficiently high intracellular EFdA-triphosphate levels. The intracellular half-life of EFdA-triphosphate in PBMCs was determined to be >72 h following a single exposure to EFdA. Daily oral administration of EFdA at low dosage levels (1 to 10 mg/kg/day) was highly effective in protecting humanized mice from HIV infection, and 10 mg/kg/day oral EFdA completely suppressed HIV RNA to undetectable levels within 2 weeks of treatment. |
| Databáze: | OpenAIRE |
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