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

Abstract

Study Question What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis? Summary Answer Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies. What is Known Already Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials. Study Design, Size, Duration This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 μg/20 μg [low dose], ATZ/LNG 1000 μg/30 μg [mid dose] or ATZ/LNG 1500 μg/40 μg [high dose]) for two consecutive 28-day wearing periods without a treatment break. Participants/Materials, Setting, Methods Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels. Main Results and the Role of Chance At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 μg/l for the low dose, 0.269 and 19.8 μg/l for the mid dose and 0.384 and 37.3 μg/l for the high dose; results were similar at the end of the second treatment period. Over the entire treatment period, mean FLS sizes were higher in all three treatment groups than during the pretreatment cycle; more women in the mid-and high-dose groups had FLSs of at least 30 mm (32-45%) than those in the low-dose group (14-24%). Changes in the mean size of FLSs were similar to those reported for low-dose progestin-only oral contraceptives and generally resolved during the 2-month treatment period. Serum E2 levels were decreased, but only one woman in each of the mid-and high-dose groups, and no woman in the low-dose group, had a serum E2 level below 20 pg/ml in both cycles. All ATZ and LNG combinations showed good tolerability. LIMITATIONS, REASONS FOR CAUTION This was an exploratory study; no formal power calculation was performed. Wider Implications of the Findings The results of this first-in-human study of the ATZ/LNG IVR facilitated the selection of ATZ and LNG doses to be investigated in the Phase 2 studies of patients with endometriosis. STUDY FUNDING/COMPETING INTEREST The study was funded by Bayer Pharma AG. T.R. is an employee of DINOX GmbH, which received funding from Bayer Pharma AG to perform this study. M.-H.S.-M., K.W., R.N., S.K., J.K., H.S. and B.R. are or have been employees of Bayer Pharma AG. H.S. is a named inventor on EP 2 552 404 B1, a patent application relating to this work. TRIAL REGISTRATION NUMBER EudraCT number: 2011-005620-18. TRIAL REGISTRATION DATE 16 November 2011. DATE OF FIRST PATIENT'S ENROLMENT 14 March 2012.