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. 2019 Dec;26(1):586-594.
doi: 10.1080/10717544.2019.1622609.

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

Rüdiger Nave  1
Affiliations

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

Rüdiger Nave. Drug Deliv. 2019 Dec.

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 µg 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.

Keywords: Clinical pharmacokinetics; drug delivery; gynecology; women's health.

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Figures

Figure 1.
Figure 1.
Intervaginal rings (IVR): (A) Monkey IVRs releasing ATZ; (B) Human IVRs releasing ATZ and LNG (54 mm diameter).
Figure 2.
Figure 2.
Mean (SD) ATZ plasma concentration time profiles after IVR insertion in female cynomolgus monkeys and young women.
Figure 3.
Figure 3.
Mean (SD) concentration of LNG in plasma following insertion of an IVR (ATZ/LNG 1050/40 µg/d) on day 9 and after 4 weeks [top] and following repeated oral LNG doses (30 µg/d) for 4 weeks [bottom]. Dotted line: average concentration (C av) p.o. in steady state.
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Grants and funding

The studies were funded by Bayer AG.

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