Pharmacokinetics and Tolerability of a Novel 17β-Estradiol and Progesterone Intravaginal Ring in Sheep.

Autor: Weiss H; Todos Medical, Ltd., West Hempstead, New York 11552., Martell B; Department of General Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520., Constantine GD; EndoRheum Consultants, Malvern, Pennsylvania 19355., Davis SM; Charles River Laboratories, Inc., Mattawan, Michigan 49071., Vidal JD; Charles River Laboratories, Inc., Mattawan, Michigan 49071., Mayer PR; Consultant, West Chester, Pennsylvania 19380., Doorbar M; Research and Development, Crossways Pharma Ltd., Thatcham, UK., Friend DR; Daré Bioscience, Inc., San Diego, California 92122. Electronic address: Dfriend@darebioscience.com.
Jazyk: angličtina
Zdroj: Journal of pharmaceutical sciences [J Pharm Sci] 2019 Aug; Vol. 108 (8), pp. 2677-2684. Date of Electronic Publication: 2019 Apr 05.
DOI: 10.1016/j.xphs.2019.03.032
Abstrakt: This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17β-estradiol (E 2 ) and progesterone (P), in drug-naïve ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E 2 and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 μg/d E 2 , respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 μg/d E 2 with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 μg E 2 and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E 2 and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.
(Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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