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

Abstract

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.

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

“…As a result, these doses were selected for the phase 2 dose-finding study. 8 It should be noted that for these simulations it was anticipated that there would be no effect of ATZ on LNG. However, potential DDIs have not been clinically investigated to date, as an IVR administering only LNG was not included in the phase 1 program.…”

Role of Aromatase Inhibitor in Endometriosis

“…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].…”

Preparation and in vitro/in vivo evaluation of anastrozole reservoir‐type intravaginal ring

“…In addition, the results show that ATZ is appropriate for a polymer vaginal drug delivery system and absorbed into blood by vaginal mucosa. ATZ IVRs can also be applied in the treatment of EM (Reinecke, Schultze‐Mosgau, Nave, Schmitz, & Ploeger, ). The drug located near the treatment site improved the partial drug concentration in blood and the treatment effect is more apparent with fewer side effects.…”