Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

Hurwitz, Selwyn J.; Asif, Ghazia; Fromentin, Emilie; Tharnish, Phillip M.; Schinazi, Raymond F.

doi:10.1128/aac.01209-09

Cited by 7 publications

(5 citation statements)

References 51 publications

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“…There were no serious adverse events and no treatment discontinuations. Likewise, the pharmacokinetic data from this study did not show any drug-drug interactions [28]. This apparently benign tolerability profile and the potent antiviral activity observed in this study makes amdoxovir plus zidovudine a promising NRTI combination product.…”

Section: Discussionsupporting

confidence: 53%

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Murphy

Kivel²,

Zala

et al. 2010

Antiviral Therapy

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Section: Discussionsupporting

confidence: 53%

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Murphy

Kivel²,

Zala

et al. 2010

Antiviral Therapy

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“…DXG was evaluated in the presence of AZT in macrophages (42,43). The cellular accumulation of DXG-TP and AZT-TP were unaffected by coincubation (Table 2), supporting similar findings in activated lymphocytes and lending further incentive for the development of this drug combination (44).…”

Section: Discussionmentioning

confidence: 58%

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Gavegnano

Detorio

Bassit

et al. 2013

Antimicrob Agents Chemother

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Understanding the cellular pharmacology of antiretroviral agents in macrophages and subsequent correlation with antiviral potency provides a sentinel foundation for definition of the dynamics between antiretroviral agents and viral reservoirs across multiple cell types, with the goal of eradication of HIV-1 from these cells. Various clinically relevant nucleoside antiviral agents, and the integrase inhibitor raltegravir, were selected for this study. The intracellular concentrations of the active metabolites of the nucleoside analogs were found to be 5-to 140-fold lower in macrophages than in lymphocytes, and their antiviral potency was significantly lower in macrophages constitutively activated with macrophage colony-stimulating factor (M-CSF) during acute infection than in resting macrophages (EC 50 , 0.4 to 9.42 M versus 0.03 to 0.4 M, respectively). Although tenofovirtreated cells displayed significantly lower intracellular drug levels than cells treated with its prodrug, tenofovir disoproxil fumarate, the levels of tenofovir-diphosphate for tenofovir-treated cells were similar in lymphocytes and macrophages. Raltegravir also displayed significantly lower intracellular concentrations in macrophages than in lymphocytes, independent of the activation state, but had similar potencies in resting and activated macrophages. These data underscore the importance of delivering adequate levels of drug to macrophages to reduce and eradicate HIV-1 infection.

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“…Similarly, amdoxovir, the orally absorbed amine prodrug of beta-D-dioxolane guanosine (DXG) is rapidly absorbed and deaminated to the active NAI by ubiquitous adenosine deaminase, producing a ratio of areas under the plasma concentration versus time curves (AUC ratio), amdoxovir: DXG of 20 : 80% ( Fig. 2) [29]. Although HIV-1 acute infections primarily involve CD4 þ lymphocytes, other tissues (e.g., lymphatic tissues and central nervous system) may also contribute to disease morbidity, and could serve as viral sanctuaries and reservoirs of infection [11 & ].…”

Section: Key Pointsmentioning

confidence: 97%

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

Hurwitz

Schinazi

2013

Current Opinion in HIV and AIDS

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Prodrug strategies can address the issues of poor oral bioavailability and delivery of active metabolites to the targeted cells. Additionally, NAPs demonstrate potential for improving deficiencies in oral absorption, metabolism, tissue distribution, cellular accumulation, phosphorylation, and overall potency, in addition to diminishing potential for in-vivo selection of resistant viruses. NAPs continue to be the backbone for the treatment of HIV and HBV, herpesviruses, and adenovirus infections because their active forms are potent, have long intracellular half-lives and are relatively safe with high barrier to resistance.

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Lack of Pharmacokinetic Interaction between Amdoxovir and Reduced- and Standard-Dose Zidovudine in HIV-1-Infected Individuals

Cited by 7 publications

References 51 publications

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals

Cellular Pharmacology and Potency of HIV-1 Nucleoside Analogs in Primary Human Macrophages

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

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