The Effect of Drug Content Reduction on the In Vitro and In Vivo Properties of Levonorgestrel-Releasing Intravaginal Rings

Nave, Ruediger; Jalkanen, Tero; Talling, Christine; Kaneko, Motohide; Matsuki, Shunji; Höchel, Joachim

doi:10.1016/j.xphs.2017.11.009

Cited by 6 publications

(16 citation statements)

References 25 publications

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“…The IVRs were made of silicone elastomer with an outer diameter of 54 mm and a cross‐sectional diameter of 5 mm as described previously . The outer surface of the ring is covered with an elastomeric membrane controlling drug release.…”

Section: Methodsmentioning

confidence: 99%

“…The IVRs were made of silicone elastomer with an outer diameter of 54 mm and a cross-sectional diameter of 5 mm as described previously. 3,7,12 The outer surface of the ring is covered with an elastomeric membrane controlling drug release. The core of the ring is composed of individual elastomer segments including 1 containing ATZ, 1 containing LNG, and several segments without drug.…”

Section: Treatmentsmentioning

confidence: 99%

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Absence of Drug‐Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial

Nave

Mellinger

Klein

et al. 2019

The Journal of Clinical Pharma

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Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4‐week wearing period has been considered for long‐term treatment of endometriosis‐associated pelvic pain. A randomized, parallel‐group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 μg/day alone or in combination with ATZ 300 μg/day, 600 μg/day, or 1050 μg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 μg/L at 300, 600, and 1050 μg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85‐1.19], 1.03 [0.88‐1.20], 0.94 [0.80‐1.10]). In conclusion, our data indicate there is no evidence of drug‐drug interaction of ATZ on LNG.

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Section: Methodsmentioning

confidence: 99%

Section: Treatmentsmentioning

confidence: 99%

Absence of Drug‐Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial

Nave

Mellinger

Klein

et al. 2019

The Journal of Clinical Pharma

Self Cite

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“…The IVRs contain excess drug to enable a steady drug release. For example, the average LNG content in IVRs releasing 40 µg/d in early clinical studies was 177 mg. New LNG formulations developed to have a similar in vitro release rate profile, but a significantly lower LNG content have been designed (Nave et al., 2018). One key difference includes the smaller thickness of the drug-containing layer in the revised formulation that maintaines an average LNG content of 10.6 mg while using the same membrane for controlled drug release.…”

Section: Methodsmentioning

confidence: 99%

“…A phase 1 DDI study was performed to investigate the effect of an intravaginally administered antimycotic, antibiotic, and a spermicide plus the co-usage of tampons on the PK of LNG and ATZ (Nave et al., 2018). In this parallel group, randomized, open-label study, healthy premenopausal women received an IVR releasing 1050 μg/d ATZ and 40 μg/d LNG as the main treatment for at least 16 days.…”

Section: Methodsmentioning

confidence: 99%

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

Nave

2019

Drug Delivery

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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.

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In vitro release testing methods for drug-releasing vaginal rings

Boyd

Variano

Spence

et al. 2019

Journal of Controlled Release

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Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastics or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since the a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring ®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drugreleasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.

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The Effect of Drug Content Reduction on the In Vitro and In Vivo Properties of Levonorgestrel-Releasing Intravaginal Rings

Cited by 6 publications

References 25 publications

Absence of Drug‐Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial

Absence of Drug‐Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial

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

In vitro release testing methods for drug-releasing vaginal rings

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