A Randomized, Double-Blind, Placebo-Controlled, First-Time-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects.

GSK3389404 is a liver-targeted antisense oligonucleotide that inhibits synthesis of hepatitis B surface antigen and all other hepatitis B virus proteins. This first-in-human, randomized, double-blind, phase 1 study assessed the safety and pharmacokinetics of GSK3389404 administered subcutaneously (SC) in healthy subjects. Four single ascending-dose cohorts (10 mg, 30 mg, 60 mg, and 120 mg) and 3 multiple ascending-dose cohorts (30 mg, 60 mg, and 120 mg once weekly for 4 weeks) each comprised 6 subjects randomized to GSK3389404 and 2 subjects randomized to placebo. There were no serious adverse events (AEs) or withdrawals due to AEs. The safety profile did not worsen with repeated dosing. The most frequent treatment-related AEs were injection site reactions (19.0% [n = 8/42], frequency unrelated to dose levels); all were mild (Grade 1) and resolved without dose modification or discontinuation. GSK3389404 administered subcutaneously was readily absorbed with a time to maximum plasma concentration (Tmax ) of 1-4 hours and an elimination half-life of 3-6 hours in plasma. Plasma area under the concentration-time curve (AUC) and maximum observed concentration (Cmax ) were dose-proportional. Dose-normalized plasma AUC from time 0 to infinity averaged 69.9 ng·h/(mL·mg dose) across cohorts, and Cmax 9.5 ng/(mL·mg dose). Pharmacokinetic profiles and parameters were comparable between single and multiple dosing. No accumulation was observed with once-weekly dosing. The metabolite was undetectable in urine and plasma. In the pooled urine, GSK3389404 was estimated to account for <0.1% of the total dose. In summary, GSK3389404 dosing has been tested up to 120 mg for 4 weeks with an acceptable safety and pharmacokinetic profile, supporting further clinical investigation in patients with chronic hepatitis B.

Pharmacokinetics of hepatitis C virus NS5A inhibitor JNJ-56914845 (GSK2336805) in subjects with hepatic impairment.

JNJ-56914845 (GSK2336805) is a hepatitis C virus nonstructural protein 5A inhibitor under development for the treatment of chronic hepatitis C (CHC) infection. This open-label, parallel-group, 2-part study evaluated the pharmacokinetics and safety of a single oral 60 mg dose of JNJ-56914845 in 4 cohorts: healthy, mild, moderate, and severe hepatic impairment (n = 8/cohort). Severity of hepatic impairment was categorized using Child-Pugh score, and the healthy subjects were matched for age, sex, body mass index, and smoking status to the moderate hepatic impairment cohort. JNJ-56914845 plasma AUC0-∞ was 26%, 52%, and 45% lower in subjects with mild, moderate, and severe hepatic impairment, respectively, relative to healthy subjects with no difference in half-life among the groups. The apparent oral clearance and volume of distribution were higher in subjects with hepatic impairment. The lower plasma concentrations were largely explained by decreased plasma protein binding in hepatically impaired subjects. One subject with severe hepatic impairment had 2 non-drug-related serious adverse events: an esophageal bleed requiring hospitalization, encephalopathy. Although hepatically impaired subjects have lower exposures than healthy matched controls, they had similar or slightly higher exposures than those observed in past studies of noncirrhotic, CHC patients, suggesting that no dose adjustments for hepatic impairment will be needed.

Use of accelerometers in a large field-based study of children: protocols, design issues, and effects on precision.

BACKGROUND: Objective methods can improve accuracy of physical activity measurement in field studies but uncertainties remain about their use. METHODS: Children age 11 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), were asked to wear a uni-axial accelerometer (MTI Actigraph) for 7 days. RESULTS: Of 7159 children who attended for assessment, 5595 (78%) provided valid measures. The reliability coefficient for 3 days of recording was .7 and the power to detect a difference of 0.07 SDs (P 90%. Measures tended to be higher on the first day of recording (17 counts/min; 95% CI, 10-24) and if children wore the monitor for fewer days, but these differences were small. The children who provided valid measures of activity were different from those who did not, but the differences were modest. CONCLUSION: Objective measures of physical activity can be incorporated into large longitudinal studies of children.

Calibration of an accelerometer during free-living activities in children.

OBJECTIVE: The aims of this study were to develop an equation to predict energy expenditure and to derive cut-points for moderate and vigorous physical activity intensity from the Actigraph accelerometer output in children aged 12 years. METHODS: The children performed a series of activities (lying, sitting, slow walking, fast walking, hopscotch and jogging) while wearing an Actigraph and a portable metabolic unit. The sample was divided into a developmental and a validation group. Random intercepts models were used to develop a prediction equation in the developmental group. The equation was assessed in the validation group by calculating limits of agreement (actual minus predicted energy expenditure). Thresholds for moderate and vigorous activity were derived by refitting the energy expenditure model with VO2 as the outcome. RESULTS: The developmental group comprised 163 children, while the validation group comprised 83 children. The equation, adjusted for age and gender, adequately predicted energy expenditure from accelerometer counts. Physical activity intensity cut-points were derived from resting VO2. The lower threshold for moderate intensity (four METs), adjusted for age and gender, was 3581 counts per minute. The lower threshold for vigorous activity (six METs) was 6130 counts per minute. CONCLUSION: The prediction equation and the derived cut-points will help to better interpret the output of the Actigraph in children aged 12 years. The cut-point for moderate to vigorous physical activity is higher than that reported previously.

Intraindividual variation of objectively measured physical activity in children.

PURPOSE: This study examined the seasonal and intraindividual variation in objectively measured physical activity in 11- to 12-yr-olds. METHODS: Children were asked to wear a uniaxial accelerometer for 7 d four times throughout the course of about a year. A random-intercepts model was used to separate the inter- and intraindividual components of physical activity. Gender, age, body mass index (BMI), height, and month of measurement were fitted to the model as potential confounders. RESULTS: A total of 315 children had valid data for at least two measurement occasions, and 244 had data for all four measurement occasions. The unadjusted intraclass correlation coefficient (ICC) for total activity (counts per minute) was 0.54; 0.49 after adjusting for gender, age, and BMI; and 0.53 after adjusting for gender, age, BMI, and month. Further adjustment for pubertal status at baseline had no effect on the ICC. Restricting the analysis to only those with data for all four measurement occasions (N=244), or to measurements taken on school days only, had no effect on the ICC. The fully adjusted ICC was 0.51 for weekdays only and 0.39 for weekend days only. For minutes of moderate to vigorous physical activity, minutes of vigorous activity, minutes of sedentary behavior, and number of 30-min blocks of sedentary behavior, the fully adjusted ICC were 0.45, 0.37, 0.59, and 0.39, respectively. The analysis was repeated for boys and girls separately, but the differences in ICC were small. CONCLUSION: There was substantial intraindividual variation in the objectively measured physical activity of these children. Studies using single a measurement occasion where physical activity is the exposure should take this into account to adjust for regression dilution.