Anemia, a frequent complication of chronic kidney disease, is most commonly treated with recombinant human erythropoiesis-stimulating agents. Oral administration of GSK1278863, a prolyl hydroxylase inhibitor, results in the accumulation of hypoxia-inducible factor 1α, and stimulates erythropoiesis by triggering the pathways involved in innate hypoxia. In vitro biotransformation data indicate that GSK1278863 is primarily metabolized by CYP2C8. This study assessed the pharmacokinetics of single-dose (100 mg) GSK1278863 administered alone, or co-administered with a high-fat/high-calorie meal or steady-state gemfibrozil (a strong CYP2C8 and OATP1B1 inhibitor). Co-administration of single-dose 100 mg GSK1278863 with a high-fat/high-calorie meal did not significantly affect the plasma exposure of GSK1278863 or its 6 predominant metabolites. Co-administration of GSK1278863 with steady-state gemfibrozil resulted in an 18.6-fold increase in the area under the curve from time 0 to infinity (AUC(0-∞) ) of GSK1278863. Additionally, the maximum plasma concentration (Cmax ) and terminal elimination half-life increased 3.92- and 3.70-fold, respectively. The appearance of metabolites was delayed, and their Cmax and AUC(0-∞) were reduced by at least 90% and 62%, respectively. These findings indicate that GSK1278863 can be safely administered without regard to food. Until further studies with weaker CYP2C8 inhibitors are conducted, co-administration of GSK1278863 with CYP2C8 inhibitors should be avoided.
Aim To assess the efficacy and safety of the selective oxytocin receptor antagonist epelsiban in the treatment of premature ejaculation (PE). Methods Double-blind, randomized, parallel-group, placebo-controlled, stopwatch-monitored, phase 2, multicenter study (GSK557296; NCT01021553) conducted in men (N = 77) 18–55 years of age, with PE defined as per International Society for Sexual Medicine consensus definition. Patients provided informed consent prior to a 4-week un-medicated run-in to determine baseline intravaginal ejaculatory latency times (IELT) recorded in an electronic diary. Patients needed to make a minimum of four intercourse attempts and have a mean IELT <65 seconds to be considered for randomization. Men with moderate-to-severe erectile dysfunction were excluded from the study. Eligible patients were randomized to placebo, epelsiban 50 mg, or 150 mg, taken 1 hour before sexual activity. Active treatment IELT times were recorded in an electronic diary, along with subjective measures of intercourse satisfaction, over an 8-week treatment period. The Modified Index of Premature Ejaculation and International Index of Erectile Function were completed at study visits. Main Outcome Measures Stopwatch timed IELT recordings and a modified version of the patient-reported outcome questionnaire the IPE were used in this study to determine the effect of epelsiban when taken orally prior to intercourse in subjects diagnosed with PE. Results The baseline (mean) IELT for patients pretreatment was (0.52, 0.63, and 0.59 minutes) for placebo, epelsiban 50 mg and 150 mg, respectively. On-treatment, average geometric least squares means of the median IELT values (mean) were slightly higher in the 50 mg and 150 mg groups (0.72 and 0.69 minutes), respectively, vs. the placebo group (0.62 minutes). Headache was the most common adverse event, and rates were similar across all groups. Conclusions Epelsiban 50 mg and 150 mg were well tolerated, but did not result in a clinically or statistically significant change in IELT in men with PE, compared with placebo.
Aim The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. Methods This was a randomized, double‐blind, placebo‐controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 300/7 and 356/7 weeks’ gestation with an uncomplicated singleton pregnancy in an in‐patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. Results Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. Conclusions Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non‐significant increase in uterine quiescence and a favourable safety profile.
An open-label single- and repeat-dose study was conducted to investigate the pharmacokinetics, safety, and tolerability of ascending doses of epelsiban in healthy female volunteers (n = 48). The pharmacokinetics of the epelsiban metabolite, GSK2395448, were also assessed. Epelsiban was readily absorbed and parent and metabolite readily appeared in plasma. The parent drug's median tmax was approximately 0.5 hours, and the metabolite's median tmax ranged from 0.5 to 1.0 hours post-parent dosing. Both epelsiban and GSK2395448 had rapid elimination half-lives, ranging between 2.66 and 4.85 hours. The metabolite:parent ratios for exposure (AUC and Cmax ) ranged from approximately 70% to greater than 100%, and therefore, GSK2395448 is considered a major metabolite of epelsiban. Mean epelsiban and GSK2395448 AUC values increased in a dose-proportional manner following both single-dose administration from 10 to 200 mg and repeat administration from 10 to 150 mg following twice daily or 4-times-daily dosing. Single-dose epelsiban pharmacokinetics in women was similar to single-dose pharmacokinetics previously observed in men. Epelsiban was generally well tolerated, and no events of clinical concern were observed in volunteers dosed in this study. The safety findings were consistent with the previous study in men, with headache the most commonly reported adverse effect.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.