title: 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.
authors.affiliation: DD Clinical Pharmacometrics, Bayer AG, Berlin, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Reinecke
authors.affiliation: DD Clinical Pharmacokinetics, Bayer AG, Berlin, Germany.
authors.forename: Marcus-Hillert
authors.initials: MH
authors.lastname: Schultze-Mosgau
authors.affiliation: DD Clinical Pharmacokinetics, Bayer AG, Berlin, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Nave
authors.affiliation: Development Gynecologic Therapies, Bayer AG, Berlin, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmitz
authors.affiliation: DD Clinical Pharmacometrics, Bayer AG, Berlin, Germany.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D000077384:Anastrozole; D003198:Computer Simulation; D003271:Contraceptive Agents, Female; D004338:Drug Combinations; D004347:Drug Interactions; D004715:Endometriosis / Q000188:drug therapy; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006080:Ovarian Follicle / Q000187:drug effects; D012738:Sex Hormone-Binding Globulin / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D003271:Contraceptive Agents, Female; D004338:Drug Combinations; D009570:Nitriles; D012738:Sex Hormone-Binding Globulin; D014230:Triazoles; D000077384:Anastrozole; D004958:Estradiol; D016912:Levonorgestrel
keywords: anastrozole; endometriosis; intravaginal ring; levonorgestrel; pharmacokinetics