Abstract 1.  Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [14C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200–800 mg), intramuscularly or subcutaneously, in a separate study. Metabolism, distribution and excretion of [14C]cabotegravir were also investigated in mice, rats and monkeys. 3. Recovery of radioactivity in humans represented a mean total of 85.3% of the dose, including 26.8% in the urine. The mean apparent terminal phase half-life was similar for both cabotegravir and radioactivity, 39 h compared to 41 h. 4. Following oral, intramuscular and subcutaneous administration, cabotegravir was the major component in plasma and the glucuronic acid conjugate (M1) represented the predominant component in urine. Cabotegravir was present in bile along with its major metabolite (M1). 5. The primary metabolite of [14C]cabotegravir in mouse, rat and monkey was the same as that in human. In vitro phenotyping experiments demonstrated that cabotegravir was metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9.

1. Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12 mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28 L/kg, respectively) with terminal elimination half-life approximately 6 h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.2. Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.3. Following oral administration to rats, [14C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24 h.4. The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.

GSK1265744 (GSK744) is an integrase strand-transfer inhibitor that has been formulated as a long-acting (LA) injectable suitable for monthly to quarterly clinical administration. GSK744 LA was administered at two time points 4 weeks apart beginning 1 week before virus administration, and macaques were challenged weekly for 8 weeks. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all animals against repeated low-dose challenges. In a second experiment, macaques were given GSK744 LA 1 week before virus administration and challenged repeatedly until infection occurred. Protection decreased over time and correlated with the plasma drug levels. With a quarterly dosing schedule in humans, our results suggest that GSK744 LA could potentially decrease adherence problems associated with daily preexposure prophylaxis (PrEP).

, 1148 (2014); 343 Science et al. Henry Chung Drosophila in A Single Gene Affects Both Ecological Divergence and Mate Choice This copy is for your personal, non-commercial use only. clicking here. colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others here. following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles ): March 11, 2014 www.sciencemag.org (this information is current as of The following resources related to this article are available online at http://www.sciencemag.org/content/343/6175/1148.full.html version of this article at: including high-resolution figures, can be found in the online Updated information and services, http://www.sciencemag.org/content/suppl/2014/02/12/science.1249998.DC1.html can be found at: Supporting Online Material http://www.sciencemag.org/content/343/6175/1148.full.html#ref-list-1 , 6 of which can be accessed free: cites 27 articles This article http://www.sciencemag.org/cgi/collection/evolution Evolution subject collections: This article appears in the following

This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-I subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (-1.33 log(10) IU/mL) compared with placebo (-0.09 log(10) IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (-0.47 log(10) copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (C-max) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and C-max of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

GW695634 is the prodrug of GW678248, a novel non-nucleoside reverse transcriptase inhibitor with potent antiviral activity against HIV/AIDS efavirenz- and nevirapine-resistant viruses. In mice, rats, and monkeys following oral administration of [(14)C]GW695634, the primary pathway of metabolic clearance was by amide hydrolysis and the main route of elimination (46%-75% of the dose) was in the feces. The primary metabolic pathway of clearance for GW695634 and GW678248 in the preclinical species was by amide hydrolysis. At least six metabolites were observed that were the products of GW695634 and GW678248 amide hydrolysis.

GSK1265744 (GSK744) is an integrase strand-transfer inhibitor that has been formulated as a long-acting (LA) injectable suitable for monthly to quarterly clinical administration. GSK744 LA was administered at two time points 4 weeks apart beginning 1 week before virus administration, and macaques were challenged weekly for 8 weeks. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all animals against repeated low-dose challenges. In a second experiment, macaques were given GSK744 LA 1 week before virus administration and challenged repeatedly until infection occurred. Protection decreased over time and correlated with the plasma drug levels. With a quarterly dosing schedule in humans, our results suggest that GSK744 LA could potentially decrease adherence problems associated with daily preexposure prophylaxis (PrEP). The global HIV-1 pandemic remains a public health problem of unprecedented proportions. There were 2.3 million new infections in 2012, with an estimated 35.3 million people already infected (1). Because an effective vaccine remains elusive, multiple clinical trials have been performed to evaluate the efficacy of various anti-retrovirals as preexposure prophylaxis (PrEP). The CAPRISA 004, the Chemoprophylaxis for HIV Prevention in Men (iPrEx), the PartnersPrEP, and the TDF2 studies have shown that topical or oral PrEP agents reduced the risk of HIV-1 infection, with efficacies ranging from 39 to 75% (2–5). The variability in efficacy likely resulted from adherence differences among the study populations. In the iPrEx study, the efficacy of daily oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) increased from 44% in all participants assigned to treatment to 90% in those participants with detectable drug in plasma (3). In a follow-up pharmacokinetic (PK) study, intracellular drug concentrations achieved from two, four, or seven directly observed doses of oral FTC/TDF per week correlated with 76%, 96%, or 99% efficacy in the iPrEx study, respectively (6). In contrast, the FEM-PrEP and the VOICE PrEP trials were stopped because of futility, and in both studies plasma drug concentrations revealed that <30% of participants were adherent to the dosing regimen (7, 8). We hypothesize that long-acting (LA) anti-retroviral formulations requiring infrequent dosing could improve adherence and thus PrEP efficacy. GSK1265744 (GSK744) is an analog of dolutegravir, a recently approved integrase strand-transfer inhibitor with a favorable efficacy and safety profile in several treatment trials (9–15). About 2600 patient years of exposure (median duration of 590 days, range from 1 to 1031) were accrued during phase 2b to 3b dolutegravir clinical trial programs. GSK744 …