A Phase 1 Study to Assess the Relative Bioavailability, Food Effect, and Safety of a Tablet Formulation of GSK2838232, a Novel HIV Maturation Inhibitor in Healthy Participants After Single and Repeated Doses.

GSK2838232 is a novel, potent HIV-1 maturation inhibitor for use in regimen-based combination antiretroviral therapy from a once-daily oral dose boosted with a pharmacoenhancer (ritonavir or cobicistat). This phase 1 study in healthy participants was conducted in 2 parts. Part 1 (n = 14) assessed the relative bioavailability of single doses of a 200-mg GSK2838232 tablet and capsule formulation boosted with 100 mg ritonavir in fed and fasted (tablet-only) subjects. Part 2 (n = 10) assessed the pharmacokinetics of repeated 500-mg once-daily doses of GSK2838232 without a pharmacoenhancing boosting agent. In part 1, GSK2838232 demonstrated comparable bioavailability following a single dose of 200 mg GSK2838232 as capsule and tablet formulations in combination with ritonavir (RTV) under fed conditions, with lower intrasubject variability observed for the tablet formulation. In part 2, following administration of 500 mg GSK2838232 once daily for 11 days under fed conditions, Cmax , AUC0-τ , and Cτ showed a small degree of accumulation (1.2- to 1.3-fold) of GSK2838232. The median tmax was approximately 4 hours on both day 1 and day 11 when given with food. The mean t½ was approximately 23 hours on day 11. Steady-state concentrations were achieved by day 3 with a geometric mean steady-state Cτ on day 11 of 28 ng/mL. The tablet formulation was generally well tolerated as a single 200-mg dose with RTV under fed and fasted conditions and following administration of multiple daily doses (11 days) of 500 mg unboosted.

Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study.

PURPOSE: Interest in Toll-like receptor (TLR) agonists for cancer treatment has been renewed after promising preliminary clinical data in combination with checkpoint inhibitors. This first-in-human study assessed the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of intravenous GSK1795091, a synthetic TLR4 agonist, in healthy volunteers as a precursor to evaluation in patients with cancer. METHODS: Healthy participants were randomized (1:3; double-blinded manner) to receive placebo or a single intravenous injection of GSK1795091 at doses of 7-100 ng. The primary objective was to evaluate the safety and tolerability of GSK1795091; secondary and exploratory objectives were to characterize GSK1795091 PK and PD properties. FINDINGS: Forty participants received study treatment (10 received placebo and 30 received GSK1795091). Overall, 3 of the 10 participants (30%) who received placebo and 16 of the 30 (53%) who received GSK1795091 experienced ≥1 adverse event (AE). The most common AEs were influenza-like illness, headache, back pain, and increased body temperature. One participant experienced late-occurring AEs (alanine aminotransferase and aspartate aminotransferase increases), considered possibly related to GSK1795091. No serious AEs were reported. GSK1795091 PK properties were characterized by dose proportional increase in exposure. Transient and dose-dependent changes in induced cytokine and chemokine concentrations and immune cell counts were observed 1-4 h after GSK1795091 administration and returned to baseline within 24 h. IMPLICATIONS: Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. These results supported the design and initiation of a repeat-dose study of intravenous GSK1795091 in combination with other immunotherapies in patients with advanced cancer. ClinicalTrials.gov identifier: NCT02798978.

Using qualitative and co-design methods to inform the development of an intervention to support and improve physical activity in childhood cancer survivors: a study protocol for BEing Active after ChildhOod caNcer (BEACON).

INTRODUCTION: Childhood cancer survivors (CCSs) treated with cardiotoxic cancer treatments are at increased risk of developing cardiometabolic complications. This risk is further exacerbated by poor health behaviours. In particular, CCSs are less active than non-cancer comparators. Existing interventions aiming to improve physical activity (PA) levels in CCSs are methodologically weak. The aim of this study is to rigorously and systematically develop an evidence-based and theoretically-informed intervention to promote, support, improve and sustain PA levels in CCSs, with the long-term goal of reducing CCSs' cardiovascular morbidity and mortality. METHODS AND ANALYSIS: The BEing Active after ChildhOod caNcer (BEACON) study involves two workpackages at two National Health Service sites in England, UK.Participants will be CCSs and their parents, and healthcare professionals (HCPs) involved in their care.Workpackage one (WP1) will use qualitative methods to explore and understand the barriers and facilitators to PA in CCSs. Two sets of semistructured interviews will be conducted with (1) CCSs (aged 10-24 years) and (2) parents of CCSs. WP2 will use co-design methods to bring together stakeholders (CCSs; their parents; HCPs; researchers) to develop a prototype intervention. Where possible, all data will be audio recorded and transcribed.Data from WP1 will be analysed using a thematic approach. Analysis of WP2 data will involve content analysis, and analysis of formative output and procedures. ETHICS AND DISSEMINATION: The study was approved by North East-Tyne & Wear South Research Ethics Committee (REC ref: 18/NE/0274). Research findings will be disseminated primarily via national and international conferences and publication in peer-reviewed journals. Patient and public involvement will inform further dissemination activities.

Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure.

BACKGROUND: Current therapies for anemia of chronic kidney disease (CKD) include administration of supplemental iron (intravenous and/or oral), blood transfusions and replacement of erythropoietin through the administration of recombinant human erythropoietin (rhEPO) and rhEPO analogs, each with limitations. Daprodustat is an orally active, small molecule hypoxia-inducible factor-prolyl hydroxylase inhibitor that is currently in Phase 3 clinical studies. As it is well appreciated that the kidney represents a major route of elimination of many drugs, and daprodustat will be administered to patients with advanced CKD as well as patients with end-stage kidney disease, it is important to characterize the pharmacokinetic profile in these patient populations to safely dose this potential new medicine. METHODS: The primary objective of these studies, conducted under two separate protocols and with identical assessments and procedures, was to characterize the steady-state pharmacokinetics of daprodustat and the six predominant metabolites (i.e. metabolites present in the highest concentration in circulation) in subjects with normal renal function, anemic non-dialysis (ND)-dependent CKD subjects (CKD Stage 3/4) and anemic subjects on either hemodialysis (HD) or peritoneal dialysis (PD). All enrolled subjects were administered daprodustat 5 mg once daily for 14 days (all except HD subjects) or 15 days (for HD subjects). Blood, urine and peritoneal dialysate were collected at various times for measurement of daprodustat, predominant metabolite, erythropoietin and hepcidin levels. RESULTS: The pharmacokinetic properties of steady-state daprodustat peak plasma concentration (Cmax), area under the plasma daprodustat concentration-time curve (AUC) and the time of Cmax (tmax) were comparable between all cohorts in this study. In addition, there was no clinically relevant difference in these properties in the HD subjects between a dialysis and ND day. For CKD Stage 3/4, HD (dialysis day) and PD subjects, the AUC of all daprodustat metabolites assessed was higher, while the C max was slightly higher than that in subjects with normal renal function. Over the course of the 14 or 15 days of daprodustat administration, hemoglobin levels were seen to be relatively stable in the subjects with normal renal function, CKD Stage 3/4 and PD subjects, while HD subjects had a decrease of 1.9 gm/dL. All renally impaired subjects appeared to have similar erythropoietin responses to daprodustat, with approximately a 3-fold increase in these levels. In subjects with minimal to no change in hemoglobin levels, hepcidin levels remained relatively stable. Daprodustat, administered 5 mg once daily for 14-15 days, was generally well tolerated with a safety profile consistent with this patient population. CONCLUSION: These studies demonstrated no clinically meaningful change in the pharmacokinetic properties of daprodustat when administered to subjects with various degrees of renal impairment, while for CKD Stage 3/4, HD (dialysis day) and PD subjects, the C max and AUC of all daprodustat metabolites assessed were higher than in subjects with normal renal function. Administration of daprodustat in this study appeared to be generally safe and well tolerated.

Learning in a task of complex auditory streaming and identification.

Adult humans were studied for improvements in their ability to segregate natural whole speech in background noise, in 6 test sessions spaced with a very wide range of inter-session interval (ISI) ranging from minutes to weeks apart so as to examine the effect of this parameter on initial (early) and late components of perceptual learning. Improvements were found even with spacings of 3 weeks between the punctate task sessions. All subjects showed similar total learning amounts but there were sex- and ISI-dependent differences in learning patterns, which we indexed by dividing the overall exponentially-decreasing learning pattern into an early phase between the first two sessions and a later phase between the second and sixth sessions. Males tested at all ISIs and females tested at short (2, 5 and 15 min) and long (1-21 days) ISIs showed small amounts of early-phase learning and large amounts of late-phase learning. However, females tested at intermediate (30 min and 1h) ISIs showed only early learning, i.e., faster learning given that the total learning was the same. This sex- and ISI-specific deviant pattern could be changed to the standard pattern by interposing an overnight interruption that included sleep amongst test sessions. Thus, improvement in this complex auditory streaming and identification task can occur even with very brief and widely-spaced exposure, generally through a standard pattern of slower overall learning, but also through a sex- and ISI-specific deviant pattern of very rapid early learning which can be modulated by interposed delay unlike the standard pattern.

Relative Bioavailability of Fixed-Dose Combinations of Tamsulosin and Dutasteride: Results From 2 Randomized Trials in Healthy Male Volunteers.

The relative bioavailabilities of dutasteride/tamsulosin hydrochloride 0.5 mg/0.2 mg fixed-dose combination (FDC) capsules compared with coadministered reference products (1 dutasteride 0.5-mg capsule [Avodart® ] + 1 tamsulosin hydrochloride 0.2-mg orally disintegrating tablet [Harnal D® ]) were investigated in 2 clinical trials under fasted and fed conditions (ClinicalTrials.gov NCT02184585 and NCT02509104). Both trials were open-label, randomized, single-dose, crossover studies in healthy male adults aged 18-65 years. Trial 1 evaluated 2 formulations (FDC1 and FDC2), and trial 2 evaluated a third formulation (FDC3). The primary end points were dutasteride area under the concentration-time curve from time 0 to t (AUC(0-t) ) and peak plasma concentration (Cmax ) and tamsulosin AUC(0-∞) , AUC(0-t) , and Cmax . The formulations were considered to be bioequivalent if the 90%CIs for the geometric mean ratios for each end point were within the range of 0.80-1.25. For FDC1 in trial 1, bioequivalence criteria were not met for dutasteride Cmax or AUC in the fasted state or for tamsulosin Cmax in the fasted or fed states. For FDC2 in trial 1, all bioequivalence criteria were met except for tamsulosin Cmax in the fasted state. For FDC3 in trial 2, bioequivalence criteria were met for all dutasteride and tamsulosin end points in both the fed and fasted states. Safety profiles were similar for all FDC formulations and combination treatments.

Pharmacokinetics, Safety, and Tolerability of Once-Daily Intranasal Fluticasone Furoate and Levocabastine Administered Alone or Simultaneously as fluticasone Furoate/Levocabastine Fixed-Dose Combination.

PURPOSE: The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump. METHODS: This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 µg) as a fixed-dose combination (FDC), FF (110 µg), or LEVO (200 µg) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration. RESULTS: Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups. CONCLUSIONS: These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.

Evaluation of bioequivalence of five 0.1 mg dutasteride capsules compared to one 0.5 mg dutasteride capsule: a randomized study in healthy male volunteers.

OBJECTIVE: To evaluate the bioequivalence of five 0.1 mg dutasteride capsules to one 0.5 mg dutasteride capsule in healthy adult male subjects under fasting conditions. METHODS: This was a single-center, open-label, randomized, single dose, two-way cross-over study (ClinicalTrials.gov identifier NCT01929330). Thirty-six healthy male subjects aged 18-65 years received 5 × 0.1 mg dutasteride softgel capsules and 1 × 0.5 mg dutasteride softgel capsule in a randomized order, with a minimum washout of 28 days between each drug administration. Serial blood samples were collected for the measurement of serum dutasteride concentrations by a validated HPLC-MS/MS method. Dutasteride pharmacokinetic parameters were calculated using non-compartmental analysis. Maximum concentration (Cmax) and area under the concentration-time curve to the last quantifiable concentration (AUC[0-t]) were compared between treatments. Safety and tolerability were monitored throughout the study. RESULTS: Five 0.1 mg dutasteride capsules were demonstrated to be bioequivalent to 1 × 0.5 mg dutasteride capsule, as the 90% confidence intervals for Cmax and AUC were within the accepted bioequivalence range of 0.80-1.25. The geometric least squares means ratios and associated 90% confidence intervals for 5 × 0.1 mg capsules vs 1 × 0.5 mg capsule were 1.01 (0.97-1.05) for Cmax and 0.91 (0.84-1.00) for AUC(0-t). Adverse events (AEs) were reported for 42% (15/36) and 36% (12/33) of subjects in the 5 × 0.1 mg and 1 × 0.5 mg dosing sessions, respectively. The most frequent AE for both treatments was headache. No subject had a serious AE. CONCLUSIONS: Five 0.1 mg dutasteride capsules were shown to be bioequivalent to one 0.5 mg dutasteride capsule in healthy adult male subjects under fasted conditions, suggesting that the two dose strengths can be interchanged. Both treatments were generally well tolerated in healthy male subjects.