Pharmacokinetics and renal safety of tenofovir alafenamide with boosted protease inhibitors and ledipasvir/sofosbuvir.

BACKGROUND: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. OBJECTIVES: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. METHODS: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and ß2 microglobulin (ß2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. RESULTS: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and ß2M:creatinine improved following the switch to TAF. CONCLUSIONS: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.

Black abalone (Haliotis cracherodii) population structure shifts through deep time: Management implications for southern California's northern Channel Islands.

For over 10,000 years, black abalone (Haliotis cracherodii) were an important resource in southern California, first for coastal Native Americans, then beginning in the nineteenth century, as one of the state's first commercial shellfisheries. By 1993, after years of heavy fishing, rising sea surface temperatures (SST), and the spread of withering syndrome (WS), black abalone populations declined dramatically, resulting in the closure of the Alta California fishery. After nearly 25 years of management and recovery efforts, black abalone are showing signs of ecological rebound along some Channel Island shorelines. These include the presence of juvenile abalone and increasing densities, largely from data collected by Channel Islands National Park (CINP) monitoring efforts that began in 1985.In an effort to apply deeper historical perspectives to modern fisheries management and restoration, we analyzed black abalone size data from San Miguel Island at prehistoric and historical archeological sites spanning the last 10,000 years and compared these populations to those described by CINP biologists between 1985 and 2013.We found a statistically significant relationship between SST and black abalone size distributions during the ancient record, along with dramatic shifts in population size structure toward larger individuals between the nineteenth century and modern periods. A pattern of larger mean black abalone sizes was identified during warm SSTs, when compared against intervals of cooler SSTs.Synthesis and applications. Our study provides a deep historical perspective of abalone population size distributions, patterns within these distributions through time, and parallels to modern abalone populations. Our results may help managers determine whether the current (and future) size and age structure of intertidal black abalone populations around the northern Channel Islands are "natural" and healthy, measured against the 10,000 year history of black abalone fishing in southern California.

BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells.

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.