Levonorgestrel in contraceptives and multipurpose prevention technologies

Polis, Chelsea B.; Phillips, Sharon J.; Hillier, Sharon L.; Achilles, Sharon L.

doi:10.1097/qad.0000000000001229

Cited by 14 publications

(7 citation statements)

References 36 publications

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“…After confirming that this film platform can be used to deliver drug for 1 week, DPV and LNG were co-formulated into the bioadhesive film as a potential MPT product and further evaluated in vivo. The investigation of local and systemic PK of the antiretroviral drug and progestin is regarded as a very important step in the development of MPT product [51]. The mechanism of action for DPV demands sufficient concentration in the target mucosal tissue, which is the major site for sexually transmitted HIV infection.…”

Section: Discussionmentioning

confidence: 99%

Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel

Regev

Patel

et al. 2019

Pharmaceutics

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Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could offer several benefits for users such as improved convenience, increased effectiveness, reduced cost, and decreased environmental burden. Here, we report the development, and in vitro and in vivo assessment of a bioadhesive vaginal film as a coitally-independent MPT dosage form for delivering dapivirine (DPV) and levonorgestrel (LNG) to prevent HIV infection and unintended pregnancy, respectively. After confirming the feasibility of bioadhesive film use for weekly drug delivery in vivo through colpophotography and MRI evaluation, the pharmacokinetics (PK) of DPV/LNG single entity and combination bioadhesive films was investigated in pigtailed macaques (n = 5). Both drugs from single entity or combination films were able to provide sustained drug release in vivo. The combination film showed lower local tissue clearance for DPV and exhibited significantly increased plasma concentration for LNG as compared to the single entity film. This proof-of-concept study demonstrates the ability of this novel bioadhesive film platform to deliver LNG and DPV simultaneously as an MPT product for the prevention of HIV infection and unintended pregnancy.

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Section: Discussionmentioning

confidence: 99%

Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel

Regev

Patel

et al. 2019

Pharmaceutics

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“…A number of MPT IVRs under development are based on progestin-only contraception using LNG [ 53 – 55 ]. There is growing concern, largely based on observational evidence from injectable depot medroxyprogesterone acetate (DMPA) [ 92 ], that an LNG-only regimen as part of an MPT may lead to an increased risk of HIV acquisition in women [ 93 , 94 ]. More research is needed to further investigate the potential links between hormone exposure in the vaginal mucosa and STI susceptibility, including HIV.…”

Section: Discussionmentioning

confidence: 99%

Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model

et al. 2017

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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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“…Additionally, they can counteract estrogen-driven endometrial proliferation in endometriosis and have applications in postmenopausal hormone therapy and endometrial hyperplasia and cancer [1,3,[10][11][12][13]. Recently, progestins have been implicated in the increased risk of HIV-1 acquisition, perhaps by modulating the integrity and cellular functions of the female reproductive tract and impact on immune functions, HIV-1 replication, and the vaginal microbiome [14,15]. However, "all progestins are not equal" [1], as they have different structures that alter their affinities for the progesterone nuclear receptor (PR), elicit unique intracellular signaling pathways and exhibit different potencies, metabolism, pharmacokinetics, efficacy, side effects and off-target effects [2,9].…”

Section: Introductionmentioning

confidence: 99%

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions

Houshdaran

Chen

Vallvé-Juanico

et al. 2020

IJMS

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Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P 4 ) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P 4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E 2 ) to each progestin influenced the number of differentially expressed genes and biofunctions in P 4 and MPA, while LNG and NETA signatures were more independent of E 2 . Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E 2 . Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.

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Levonorgestrel in contraceptives and multipurpose prevention technologies

Cited by 14 publications

References 36 publications

Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel

Rational Design of a Multipurpose Bioadhesive Vaginal Film for Co-Delivery of Dapivirine and Levonorgestrel

Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions

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