Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial

Schultze‐Mosgau, Marcus‐Hillert; Waellnitz, K.; Nave, Ruediger; Klein, Stefan; Kraetzschmar, Joern; Rautenberg, Tanja; Schmitz, H; Rohde, Beate

doi:10.1093/humrep/dew145

Cited by 28 publications

(45 citation statements)

References 35 publications

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“…In order to obtain a release rate that is above this cutoff for most subjects, 300 μg/d was chosen as the minimally effective dose. Selection of the highest release rate of ATZ was not limited by safety issues because there were no safety concerns at the highest dose level in the phase 1 clinical study . The highest release rate for ATZ was, however, limited by the technical feasibility of using only 1 IVR of an acceptable size in combination with 40 μg/d LNG and therefore amounted to 1050 μg/d, which was chosen as the maximum dose.…”

Section: Discussionmentioning

confidence: 99%

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Model‐Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms

Reinecke

Schultze‐Mosgau

Nave

et al. 2016

The Journal of Clinical Pharma

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Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 μg/d LNG combined with 300, 600, or 1050 μg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 μg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation.

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Section: Discussionmentioning

confidence: 99%

“…Full details of participants as well as inclusion and exclusion criteria for this study are published elsewhere . Briefly, the study consisted of a screening visit, pretreatment cycle, treatment, and follow‐up.…”

Section: Methodsmentioning

confidence: 99%

Model‐Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms

Reinecke

Schultze‐Mosgau

Nave

et al. 2016

The Journal of Clinical Pharma

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“…For this purpose, the tampons were used in group D on days 20 to 23. No parallel reference group was available for this period; however, the continuous, stable concentration–time profiles of ATZ and LNG for this period could be seen in a previous study . Interestingly, the concentrations of ATZ and LNG appeared to be slightly decreased during the use of tampons.…”

Section: Discussionmentioning

confidence: 81%

“…One phase 1 study has been completed in Europe investigating the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of IVRs delivering ATZ/LNG in healthy, ovulating women aged 18–35 years . The results showed that doses of 40 μg LNG/day combined with up to 1050 μg ATZ/day reached the anticipated exposure levels for both drugs …”

mentioning

confidence: 99%

Absence of Effect of Intravaginal Miconazole, Clindamycin, Nonoxynol‐9, and Tampons on the Pharmacokinetics of an Anastrozole/Levonorgestrel Intravaginal Ring

Nave

Klein

Müller

et al. 2017

The Journal of Clinical Pharma

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A study was performed to investigate the effect of an intravaginally administered antimycotic, an antibiotic, and a spermicide plus the co‐usage of tampons on the pharmacokinetics (PK) of levonorgestrel (LNG) and anastrozole (ATZ) administered as an intravaginal ring (IVR) releasing 1050 μg ATZ per day and 40 μg LNG per day. In this parallel‐group, randomized, open‐label study, healthy premenopausal women received an IVR as the main treatment. Comedications were administered on 3 consecutive evenings during treatment with IVR on days 9–11 (group A, 400 mg miconazole; group B, 100 mg clindamycin; group C, 75 mg nonoxynol‐9); tampon co‐usage (group D) was performed on days 20–23. The primary PK parameter was the average plasma concentration (Cav,ss) of ATZ and LNG at defined intervals, mainly prior to, during, and up to 7 days after the start of comedication. Fifty‐two subjects were included, and at least 11 subjects per group completed the treatments. Overall, the medications and comedications were safe and well tolerated. Very similar ATZ and LNG plasma levels were observed across all groups. The calculated ratios of Cav,ss confirmed the absence of PK interactions because all relevant point estimates and 90% confidence intervals were within the range of 0.800–1.250, which is typically used in bioequivalence studies. These results demonstrate the absence of PK interactions between ATZ/LNG released from IVR and the tested antibiotic, antimycotic, spermicide, and tampons. Therefore, no restrictions for the use of the IVR are needed to continue the clinical program intended to treat endometriosis symptoms.

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“…Intravaginal ring which consists of Anastrozole and Levonogestrel has been brought into experimental practice and it was proposed that constant drug plasma levels can be achieved due to the continuous release of drug from the intravaginal ring. The efficacy of intravaginal drug delivery was uncertain but it was shown that by avoiding the first-pass metabolism in the liver, equivalent efficacy could be accomplished and unwanted side effects were reduced [31,32]. In a study done on cynomolgus monkeys using the vaginal rings, the circulating estrogen level was found to be reduced by at least 30% without leading to ovarian hyperstimulation caused by the pituitary counter regulatory pathway [33].…”

Section: Pain In Endometriosismentioning

confidence: 99%

Role of Aromatase Inhibitor in Endometriosis

Yoong

2018

Journal of Asian Scientific Research

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Pharmacokinetics, pharmacodynamics, safety and tolerability of an intravaginal ring releasing anastrozole and levonorgestrel in healthy premenopausal women: a Phase 1 randomized controlled trial

Abstract: 14 March 2012.

Cited by 28 publications

References 35 publications

Model‐Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms

Model‐Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms

Absence of Effect of Intravaginal Miconazole, Clindamycin, Nonoxynol‐9, and Tampons on the Pharmacokinetics of an Anastrozole/Levonorgestrel Intravaginal Ring

Role of Aromatase Inhibitor in Endometriosis

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