5. Two subjects achieved HCV RNA <25 IU/ml. However, the pharmacokinetics and antiviral responses were highly variable. Whereas the activity results were disappointing, clinical proof of concept was observed in terms of safety. GS-6620 did have a markedly improved safety profile relative to C-Nuc1, progressing through chronic toxicology studies in rats and dogs at relatively high doses. The story

of GS-6620 illustrates both how nucleotide prodrugs enable further progression of candidates and also the complexity of predicting the behavior of nucleotide prodrugs across species. One wonders what cell culture test or animal model may have predicted such variability. When selecting famciclovir as the prodrug for penciclovir, one potential prodrug was rejected because Selleckchem Veliparib the pharmacokinetics in rats varied

widely between individual animals (Vere Hodge et al., 1989). A recent publication by Adrian and his team highlights the metabolism of GS-6620 by carboxylesterase 2, an enzyme highly expressed in the human small intestine but not uniformly expressed in different animal species, as a possible reason for the highly variable and suboptimal intestinal absorption of GS-6620 in humans (Murakami www.selleckchem.com/products/Metformin-hydrochloride(Glucophage).html et al., 2014). The focus of Adrian’s talk then switched to HIV. Over the last 15 or 20 years in North America, the HIV-infected population has been changing, becoming older (now 33% over 50 years old vs <10% in 1995) and more likely to be obese (in every USA state, >20% adults with BMI⩾30). This has led to a shift in the focus of antiretroviral therapy (ART), from solely control of HIV replication to now include tolerability in older, possibly obese, patients. The first example given for HIV was how application of a different prodrug strategy can markedly change the distribution even when delivering the same pharmacologically active nucleotide analog. The first approved prodrug

of tenofovir (TFV) was TFV disoproxil fumarate (TDF). More recently, TFV alafenamide (TAF) has been progressed into clinical development. A key difference in the properties of the two prodrugs is their stability in plasma, with half-lives of 0.4 and 90 min, respectively. Even with a short half-life, TDF gave better delivery of TFV into Gefitinib cells, as indicated by the HIV EC50 values in cell culture assays but there clearly was room for improvement; the EC50 values for TFV, TDF and TAF are 1.2, 0.015 and 0.003 μM respectively. Whereas the gain in cell culture EC50 value may be modest, this is not the only gain. The increased stability of TAF allows it to load on-target cells and tissues (e.g., lymph nodes) for a longer period of time resulting in increased lymphoid cell and tissue levels at greatly reduced circulating TFV levels, leading to less exposure to off-target tissues (e.g., kidney). In monotherapy studies after oral dosing with TDF (300 mg) and TAF (25 mg), the plasma TFV AUC is reduced from 1920 to 268 ng.