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

Abstract

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.

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

“…The PK of this high dose (ATZ/LNG 1050/40 µg/d) was characterized in a DDI study resulting in geometric mean concentrations of 24.9 µg/L at the end of the wearing period (Nave et al, 2018). Similar C trough values were observed for this dose in the phase 2b study (Nave et al., 2019). These values indicate that the systemic exposure following ∼1 mg ATZ per day using an IVR is comparable to a daily oral dose of 1 mg (Wiseman and Adkins, 1998; Schwartzberg et al., 2017; Plummer et al., 2018).…”

“…To reduce variability, the median value from 3 samples was calculated and referenced as C ss . One outcome of the PK investigation within this study was the confirmation of dose proportionality of ATZ exposure in the range of 300–1050 µg/d (Nave et al., 2019).…”

“…For LNG, stable release rates over a period of 28 days were observed for all tested dose strengths. The actual in vitro release rates were slightly above the nominal in vitro release rates of 20, 30, and 40 µg/d (Schultze-Mosgau et al., 2016; Nave et al., 2019). There is obviously no difference in the in vitro release between IVRs delivering 40 µg/d LNG with or without ATZ (Supplemental Material, Figure S2).…”

“…Overall, similar in vitro release rates for ATZ were obtained for IVRs used in the phase 2b study. Average actual in vitro release rates on day 28 of 290, 596, and 941 µg/d were reported for IVRs with nominal release rates of 300, 600, and 1050 μg/d (Nave et al., 2019).…”

“…Recently, a randomized, parallel-group, multi-center phase 2b study in women with symptomatic endometriosis has been performed investigating the PK effects of ATZ on LNG among other objectives (Nave et al., 2019). Patients were randomized to the treatment group with IVRs releasing LNG 40 µg/d alone or in combination with ATZ 300, 600, or 1050 µg/d for 12 weeks.…”