Physicochemical Properties of the Nucleoside Prodrug R1626 Leading to High Oral Bioavailability

Brandl, Michael; Wu, Xiaoyang; Holper, Marites; Lü, Hong; Jia, Zhongjiang; Birudaraj, Raj; Reddy, Micaela B.; Alfredson, Tom; Tran, Tony T.; Larrabee, Susan; Hadig, Xu; Sarma, Keshab; Washington, Carla; Hill, George; Smith, David B.

doi:10.1080/03639040701836636

Cited by 35 publications

(19 citation statements)

References 32 publications

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“…The drawback of this approach is the increased complexity of compound synthesis, formulation, and pharmacokinetic analysis, all of which could lengthen the time of drug development. As exemplified by HCV nucleoside development, early clinical candidates were all nucleoside inhibitors, but none of them progressed beyond phase III clinical trials due to unexpected toxicity or insufficient potency (Brandl et al, 2008). A phosphoramidate prodrug approach was used to overcome these issues and ultimately led to the approval of sofosbuvir for HCV treatment with excellent safety and efficacy profile (Sofia, 2013).…”

Section: Monophosphate Prodrug To Improve Intracellular Triphosphate mentioning

confidence: 99%

The search for nucleoside/nucleotide analog inhibitors of dengue virus

2015

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Section: Monophosphate Prodrug To Improve Intracellular Triphosphate mentioning

confidence: 99%

The search for nucleoside/nucleotide analog inhibitors of dengue virus

2015

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“…1A). It was originally developed as treatment against hepatitis C virus (HCV) infection (5,6). Although balapiravir exhibited potency in HCV-infected patients, its clinical development was discontinued due to unacceptable toxicity (7).…”

mentioning

confidence: 99%

Activation of Peripheral Blood Mononuclear Cells by Dengue Virus Infection Depotentiates Balapiravir

Chen

Ghafar

Karuna

et al. 2014

J Virol

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bIn a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC 50 ). Here, we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus. The elevated EC 50 was greater than the plasma trough concentration of R1479 observed in dengue patients treated with balapiravir and could possibly explain the efficacy failure. Mechanistically, dengue virus infection triggered PBMCs to generate cytokines, which decreased their efficiency of conversion of R1479 to its triphosphate form (the active antiviral ingredient), resulting in decreased antiviral potency. In contrast to the cytidine-based compound R1479, the potency of an adenosine-based inhibitor of dengue virus (NITD008) was much less affected. Taken together, our results demonstrate that viral infection in patients before treatment could significantly affect the conversion of the prodrug to its active form; such an effect should be calculated when estimating the dose efficacious for humans. Dengue virus (DENV) is the most prevalent mosquito-borne virus that causes human disease. A recent study estimated that 390 million humans are infected and that 96 million infected humans exhibit disease symptoms annually (1). No licensed vaccine or antiviral for the prevention and treatment of DENV is currently available. Upon transmission by infected mosquitoes, the virus first infects dendritic cells, spreads to lymph nodes, and disseminates to various tissues and organs. Although the sites of DENV replication in natural human infections remain to be conclusively defined, monocytes and macrophages in peripheral blood mononuclear cells (PBMCs) were reported to be major replication sites in patients (2, 3).Nucleoside analogs represent the major class of antiviral drugs in clinical use (4). To exert antiviral effects, nucleoside analogs must be converted to the triphosphate form (by host and/or viral kinases) before being incorporated into the viral DNA/RNA chain by viral polymerase. Balapiravir is an ester prodrug of the cytidine analog 4=-azidocytidine, also known as R1479 (Fig. 1A). It was originally developed as treatment against hepatitis C virus (HCV) infection (5, 6). Although balapiravir exhibited potency in HCV-infected patients, its clinical development was discontinued due to unacceptable toxicity (7). Since R1479 has anti-DENV activity in vitro, balapiravir was repurposed for a phase II trial for treatment of DENV infection. Surprisingly, no viremia reduction was observed in balapiravir-treated dengue patients, even though the maximum concentration in plasma (C max ) of R147...

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“…TubicGrodzanis et al (27) used absorption modeling to highlight the potential for favorable absorption of miconazole at particle sizes below 25 μm. More recently, Brandl et al (28) reported the use of GastroPlus™ to predict the effect of particle size across doses for the nucleoside pro-drug R1626. However, with the exception of the publication by Yu, none of the other published reports attempted to quantitatively validate the predicted particle size reduction effect.…”

Section: Assessment Of Effect Of Api Bulk Properties On Oral Absorptionmentioning

confidence: 99%

Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling

Kesisoglou

2009

AAPS J

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Abstract. Selection of API phase is one of the first decision points in the formulation development process. Subsequent to phase selection, the focus shifts to the API physical properties such as particle size. Oftentimes, such properties are closely monitored throughout the drug development, as they can have a direct impact on the formulation bioperformance. The purpose of this mini-review was to describe the potential for application of absorption modeling in understanding the effect of API properties on bioavailability. Examples are provided to demonstrate how absorption modeling can be applied both early on to set the formulation strategy as well as during the development process to help with setting of specifications around the API. Limitations of the existing models and areas of possible expansion of such tools are also discussed.

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Physicochemical Properties of the Nucleoside Prodrug R1626 Leading to High Oral Bioavailability

Cited by 35 publications

References 32 publications

The search for nucleoside/nucleotide analog inhibitors of dengue virus

The search for nucleoside/nucleotide analog inhibitors of dengue virus

Activation of Peripheral Blood Mononuclear Cells by Dengue Virus Infection Depotentiates Balapiravir

Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling

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