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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?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.

SUBMITTER: Nave R

PROVIDER: S-EPMC6567139 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Nave Rüdiger R

Drug delivery 20191201 1

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 <i>in vitro</i> release, preclinical IVR PK investigations in monkeys, and clinical PK c ...[more]

PMID: 31174438

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Project description:Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

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

Publications

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

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