Treatment of spontaneous preterm labour with retosiban: a phase II pilot dose-ranging study.

AIMS: The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 340/7 and 356/7  weeks' gestation. METHODS: In parts A and B of a three-part, double-blind, placebo-controlled, multicentre study, women were randomized 3:1 (Part A) or 2:1 (Part B) to either 12-h IV retosiban followed by a single dose of oral placebo (R-P) or 12-h IV placebo followed by single-dose oral retosiban (P-R). RESULTS: A total of 29 women were randomized; 20 to R-P and nine to P-R. An integrated analysis found that adverse events were infrequent in mothers/newborns and consistent with events expected in the population under study or associated with confounding factors. Retosiban was rapidly absorbed after oral administration, with an observed half-life of 1.45 h. Efficacy analyses included 19 women. While not statistically significant, those receiving R-P more frequently achieved uterine quiescence in 6 h (R-P, 63%; 95% credible interval [CrI]: 38, 84; P-R, 43%; 95% CrI: 12, 78) and more achieved a reduction of ≥50% in uterine contractions in 6 h (R-P, 63%; 95% CrI: 38, 84; P-R, 29%; 95% CrI: 4, 64). The number of days to delivery was increased in women receiving R-P (median 26 days for R-P vs. 13 days for P-R). CONCLUSIONS: Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL.

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women.

PURPOSE: Retosiban is a small molecule oxytocin receptor antagonist that is under evaluation in clinical studies for treatment of spontaneous preterm labor. A Thorough QT/QTc study was conducted to evaluate the effect of retosiban on cardiac repolarization according to International Conference on Harmonization E14 guidance. This was a randomized, placebo- and positive-controlled, single-dose, crossover study of healthy men and women. METHODS: All study participants received a 100 mg dose of retosiban (therapeutic target exposure), a 800 mg dose of retosiban (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), and placebo with an appropriate washout. Holter monitoring data at baseline (predose) and at 13 subsequent time points during the next 24 hours were extracted and manually read by a central ECG reader who was blinded to the treatment assignment and corrected for heart rate by using the Fridericia formula (QTcF). A linear exposure-QTc response model was developed: ΔΔQTcF=RI+Cp,R⋅RS+MI+Cp,M⋅MS, where RI and MI are intercept terms for retosiban and moxifloxacin, respectively, RS and MS are slope terms for retosiban and moxifloxacin, respectively, and Cp,R and Cp,M are plasma concentrations for retosiban and moxifloxacin, respectively. FINDINGS: A total of 52 healthy men (n = 27) and women (n = 25), with a mean age of 32 years, were enrolled in the study, and 43 (83%) completed all treatment periods and assessments. Mean placebo-corrected change from baseline QT (ΔΔQTcF) for the 2 retosiban dose groups revealed statistically significant decreases in ΔΔQTcF between 2 and 3 hours after administration, reaching a value of -2.5 msec for both retosiban dose groups. The 400 mg moxifloxacin group had a statistically significant increase in the ΔΔQTcF value at 0.75 hours after administration, reaching a maximal increase of 11.10 msec at 4 hours after administration. Results of the exposure-QTc response modeling revealed that there was no significant effect of retosiban on the ΔΔQTcF at therapeutic exposures. For the supratherapeutic exposure of retosiban, there was a slight negative effect, with a mean decrease of -3.05 msec. The moxifloxacin arm had a mean increase in ΔΔQTcF of 10.7 msec. IMPLICATIONS: At therapeutic and supratherapeutic exposures, retosiban had no significant effect on cardiac repolarization, as estimated by the ΔΔQTcF. However, both doses of retosiban had a minor shortening effect. This is not considered to be clinically significant. CLINICALTRIALS. GOV IDENTIFIER: NCT01702376.

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study.

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 30(0/7) and 35(6/7) 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.

A single- and multiple-dose study to investigate the pharmacokinetics of epelsiban and its metabolite, GSK2395448, in healthy female volunteers.

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.

Gabapentin enacarbil and morphine administered in combination versus alone: a double-blind, randomized, pharmacokinetic, and tolerability comparison.

PURPOSE: Coadministration of morphine with oral gabapentin has been shown to increase plasma gabapentin concentrations. This study evaluated whether there was any interaction between gabapentin enacarbil (GEn), which is a prodrug of gabapentin, and morphine in terms of pharmacokinetics, pharmacodynamics, safety, and tolerability. METHODS: This randomized, double-blind, 3-treatment crossover study included nonelderly, healthy male subjects. The study subjects received (in random order and with a minimum 7-day washout between treatments) the following: morphine placebo + GEn 600 mg; morphine 60 mg + GEn 600 mg; and morphine 60 mg + GEn placebo. Morphine/morphine placebo was administered in fasted conditions, and GEn/GEn placebo was administered 2 hours later with food. The primary end points were AUC and C(max) for gabapentin, morphine, and morphine-6-glucuronide. Pharmacodynamic measures were limited to subject assessment of somnolence, dizziness, and nausea conducted by using a visual analog scale (VAS). Safety monitoring included adverse event reporting, clinical laboratory tests, vital signs, pulse oximetry, and 12-lead ECGs. FINDINGS: Of the 18 enrolled subjects (mean age, 36 years), 15 (83%) completed the study. Sixteen received GEn, 15 received morphine, and 18 received the combination. Compared with the single treatments, the 90% CIs for the ratio of the geometric means for both AUC and C(max) were all within 0.8 to 1.25, the accepted range for bioequivalence. Ratios of geometric mean (90% CIs) values were as follows: gabapentin, AUC of 1.10 (1.035-1.162) and C(max) of 1.02 (0.920-1.126); morphine, AUC of 1.06 (1.014-1.098) and C(max) of 1.05 (0.967-1.134); and morphine-6-glucuronide, AUC of 0.992 (0.929-1.058) and C(max) of 0.953 (0.855-1.062). Mean changes from predose VAS scores were generally small and suggested a slight increase in dizziness after GEn and slight increases in dizziness, somnolence, and nausea after morphine. Trends were noted suggesting slightly greater score changes from predose with the combination treatment than with either drug given alone for somnolence and dizziness. Adverse events were generally mild; there were no serious adverse events or subject withdrawals due to adverse events. Headache and nausea were among the most commonly reported events for the combination and morphine treatments (headache, 27% and 28%; nausea, 13% and 11%, respectively). There were fewer adverse events with GEn alone than with either of the combination regimens. IMPLICATIONS: No significant pharmacokinetic interaction between the 2 drugs was seen in this study. The VAS data suggest that the potential exists for increased adverse effects when GEn and morphine are coadministered. ClinicalTrials.gov identifier: NCT01476124.

Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863.

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.

Cardiac repolarization with Gabapentin enacarbil in a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome. OBJECTIVE: This study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance. METHODS: This was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18-50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups. RESULTS: Of 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) Cmax (between-subject coefficient of variation) was 7.49 (21.2) µg/mL for GEn 1200 mg, 32.46 (23.9) µg/mL for GEn 6000 mg, and 2.08 (24.5) µg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%). CONCLUSION: Single doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.

Safety and efficacy of epelsiban in the treatment of men with premature ejaculation: a randomized, double-blind, placebo-controlled, fixed-dose study.

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.