Development of an intravaginal ring delivering simultaneously anastrozole and levonorgestrel: a pharmacokinetic perspective

Abstract

Intravaginal rings (IVRs) are an option for continuous administration of drugs in women. As an attractive approach for the treatment of endometriosis-associated pelvic pain, IVRs delivering a combination of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG) have been developed. This article describes the developmental pharmacokinetic (PK) aspects covering the characterization of in vitro release, preclinical IVR PK investigations in monkeys, and clinical PK considerations. An IVR for ATZ has been developed and investigated in healthy menstruating female cynomolgus monkeys showing effective in vivo release. PK data from the size-adapted IVR used in these animals can be translated into a human context as confirmed in human studies where predefined exposure levels of ATZ were reached. As ATZ may cause harm to the fetus, use of effective contraception has to be assured in women of childbearing potential. Therefore, the IVR delivers a low dose of LNG as a contraceptive. Although the daily dose differed strongly between both drugs (20 mg LNG/d to >1 mg ATZ/d), simultaneous delivery of ATZ and LNG in vitro and in vivo was observed with a high correlation between the in vitro release and PK profiles. The PK characteristics successfully guided the design of clinical studies investigating the drug-drug interaction (DDI) potential. No relevant DDI between both the investigated or other vaginally administered drugs were identified.

Medical treatments of endometriosis: a review

“…The effectiveness and tolerability of anastrozole administered through a VR in patients with endometriosis are currently under investigation in a randomized, double-blind phase IIb clinical trial (NCT02203331). The outcomes will allow us to determine whether the use of a VR may constitute a breakthrough in the use of AIs for endometriosis treatment [180] . Implants that release etonogestrel improve dysmenorrhea and pelvic pain symptoms and enhance sexual and social function in patients with endometriosis [83][84][85] .…”

Recent advances in electrospun nanofiber vaginal formulations for women's sexual and reproductive health

“…Each type of vaginal dosage form may offer certain advantages over others, depending upon the nature of the drug to be administered and the intended therapy. For example, vaginal rings can provide sustained or controlled release of highly potent steroid hormones drugs over many weeks or months (Murphy et al, 2018;Nave, 2019); aqueous vaginal gels are useful in administering relatively large doses of hydrophilic drugs (Ciolacu et al, 2020). Other advanced drug delivery systems have also been reported, including mucoadhesive or stimuli-responsive (i.e.…”