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

Stier, Brendt; Fossler, Michael J.; Liu, Feng; Caltabiano, S

doi:10.1016/j.clinthera.2015.05.007

Cited by 5 publications

(7 citation statements)

References 15 publications

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“…11 The halflife of retosiban (ß1.7 hours) is shorter than epelsiban (ß3.0 hours) as previously reported. 12 The only marketed oxytocin antagonist available is atosiban (which also has vasopressin-antagonistic properties), and as it is a peptide, it is only available via a parenteral route. In conclusion, the available safety and PK data suggest that epelsiban is generally well tolerated, with no identified risks at higher exposures that would preclude administration of total daily doses up to 900 mg, administered in divided doses BID or TID to evaluate the effect of treatment with epelsiban in women with adenomyosis in trials of longer duration.…”

Section: Discussionmentioning

confidence: 99%

“…10 Dosing in each cohort occurred sequentially. Dose escalation proceeded once preliminary safety/tolerability (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and PK data (days 1 and 7) had been reviewed for all subjects at the previous dose. Blood samples for safety and PK analysis were collected on days 1, 7, and 14 of the 14-day in-house treatment period.…”

Section: Multiple-day Dosing Studymentioning

confidence: 99%

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Single‐ and Multiple‐Day Dosing Studies to Investigate High‐Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers

Mahar

Enslin

Gress

et al. 2017

Clinical Pharm in Drug Dev

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Open-label single-and double-blind repeat-dose studies in healthy female volunteers were conducted to investigate the pharmacokinetics (PK) and safety/tolerability of epelsiban total daily doses ranging from 600 to 900 mg. In 1 study (n = 12), epelsiban was dosed at 300 or 450 mg twice daily (every 12 hours) for a single day. In the repeat-dose doubleblind study, epelsiban and placebo were administered to 31 subjects as 200 mg 3 times daily, 300 mg 3 times daily (TID), or 450 mg twice daily (BID) for 14 days. After both single and 14 daily repeat doses, the PK profiles for epelsiban and its metabolite, GSK2395448, remained linear at all administered doses. The exposures at a given total daily dose were also similar between BID and TID dosing regimens. Exposure (AUC 0-τ ), based on dosing intervals, for both epelsiban and GSK2395448 was similar. However, compared with morning dosing, C max was lower after evening dosing, possibly because of a food effect. The highest accumulation of epelsiban and GSK2395448 exposures (AUC 0-τ ) was approximately 34% for each after repeat dosing, consistent with the short half-life. At total daily doses of 600 and 900 mg, epelsiban was generally well tolerated, and there were no significant safety concerns identified.

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Section: Discussionmentioning

confidence: 99%

Section: Multiple-day Dosing Studymentioning

confidence: 99%

Single‐ and Multiple‐Day Dosing Studies to Investigate High‐Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers

Mahar

Enslin

Gress

et al. 2017

Clinical Pharm in Drug Dev

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“…Mixed model ANOVA applied by Morganroth [ 19 ] in crossover TQT study on betrixaban also included period, sequence, gender, and treatment-gender interaction as fixed terms. Mixed effects ANCOVA was used to analyze the time-matched change in QTc in crossover trials on retosiban [ 20 ], lenvatinib [ 21 ], umeclidinium and umeclidinium/vilanterol [ 22 ], dabigatran [ 23 ], and parallel trials on tafenoquine [ 24 ], and parallel group/crossover study on prucalopride [ 25 ]. Revised ANCOVA model besides random and fixed terms, accounted for baseline QTc as a covariate.…”

Section: “Top-down” Pk/pd Modelling and Simulation (M And S)mentioning

confidence: 99%

Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations

2016

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Cardiac safety is an issue causing early terminations at various stages of drug development. Efforts are put into the elimination of false negatives as well as false positives resulting from the current testing paradigm. In silico approaches offer mathematical system and data description from the ion current, through cardiomyocytes level, up to incorporation of inter-individual variability at the population level. The article aims to review three main modelling and simulation approaches, i.e. “top-down” which refers to models built on the observed data, “bottom-up”, which stands for a mechanistic description of human physiology, and “middle-out” which combines both strategies. Modelling and simulation is a well-established tool in the assessment of drug proarrhythmic potency with an impact on research and development as well as on regulatory decisions, and it is certainly here to stay. What is more, the shift to systems biology and physiology-based models makes the cardiac effect more predictable.

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“…Mean clearance values ranged from 50 to 64 L/h, with a mean half‐life (t 1/2 ) ranging from 1.7 to 2.3 hours. The oral pharmacokinetics of 100 and 800 mg retosiban in a thorough QT/QTc study have been published . The absolute bioavailability with a 100‐mg oral dose of retosiban ranged from 17% to 25% when compared with 30‐, 15‐, and 5‐minute intravenous infusions.…”

mentioning

confidence: 99%

“…The oral pharmacokinetics of 100 and 800 mg retosiban in a thorough QT/QTc study have been published. 8 The absolute bioavailability with a 100-mg oral dose of retosiban ranged from 17% to 25% when compared with 30-, 15-, and 5-minute intravenous infusions. These results suggest extensive firstpass elimination of retosiban after oral administration and is not surprising given that retosiban is a CYP3A4 substrate.…”

mentioning

confidence: 99%

A Phase 1 Randomized, Placebo‐Controlled Study Assessing the Pharmacokinetics, Safety, and Tolerability of Retosiban in Healthy, Nonpregnant Japanese Subjects

Caltabiano

Magee

Liu

et al. 2017

Clinical Pharm in Drug Dev

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This study characterized the pharmacokinetics, safety, and tolerability of retosiban in healthy, nonpregnant Japanese women prior to the enrollment of Japanese women in preterm labor in phase 3 trials. This study had 2 cohorts. Cohort 1 was a double-blind, sponsor-open, randomized study in Japanese women. Cohort 2 was an open-label study in white women to compare the pharmacokinetics with those of Japanese women.Retosiban was administered as a 6 mg/h infusion for 24 hours, followed by a 12 mg/h infusion over the next 24 hours; each infusion was preceded by a 6 mg loading dose administered over 5 minutes. Plasma concentrations of retosiban and its major metabolite, GSK2847065, were determined with an informal comparison of pharmacokinetics between Japanese and white women. There was minimal difference in exposure to retosiban or GSK2847065 between Japanese and white women (ratio of 1.03 in retosiban AUC and C max ). The 2 doses of retosiban were well tolerated across both populations, and no ethnic difference was observed in the safety profile. Given the results of this study and the known safety profile and dosing flexibility in the phase 3 trials, ethnic-specific dose adjustment of retosiban is not considered necessary for the Japanese and general Asian population.

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

Cited by 5 publications

References 15 publications

Single‐ and Multiple‐Day Dosing Studies to Investigate High‐Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers

Single‐ and Multiple‐Day Dosing Studies to Investigate High‐Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers

Top-down, Bottom-up and Middle-out Strategies for Drug Cardiac Safety Assessment via Modeling and Simulations

A Phase 1 Randomized, Placebo‐Controlled Study Assessing the Pharmacokinetics, Safety, and Tolerability of Retosiban in Healthy, Nonpregnant Japanese Subjects

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