Isabel Reinecke (1), Rüdiger Nave (2), Marcus-Hillert Schultze-Mosgau (2), Heinz Schmitz (3), Bart Ploeger (1)
(1) DD Clinical Pharmacometrics; (2) DD Clinical Pharmacokinetics; (3) Development Gynecologic Therapies; (1)-(3) Bayer Pharma AG, Berlin, Germany
Objectives: During treatment with low-dose levonorgestrel (LNG) for contraception in clinical phase I studies, fluctuations over time were observed in LNG plasma concentrations which cannot be described with help of the product’s release profile and PK model. These fluctuations were even more distinct for the PD parameter serum sex hormone binding globulin (SHBG) which interacts with LNG. Endogenous estradiol (E2) concentrations are positively correlated with SHBG concentrations in premenopausal women [1]. However, fluctuations in LNG concentrations during treatment with low-dose LNG containing contraceptives as a result of these interactions have not been well described. The goal of this analysis was to describe the PK of LNG in a phase I study investigating LNG releasing intravaginal rings (IVRs) and in particular to explain the fluctuations in the LNG concentrations.
Methods: The pharmacokinetics (PK) of LNG was assessed in an open-label phase I study where the use of LNG releasing IVRs in dose range of 20 to 40µg/d was investigated over 56 days, ring change after 28 days, in 66 healthy young women by developing a population PK model using NONMEM (version 7.2.0). In order to describe the fluctuations, the assumption that E2 has an effect on SHBG was considered by including E2 measurements as covariate in the model.
Results: The PK of LNG was described by a two-compartment model including the interaction of LNG and SHBG where a turnover model for SHBG was used. SHBG concentrations followed the observed increase and decrease in E2 concentrations shortly thereafter indicating that E2 has a stimulating, delayed effect on SHBG concentrations, with higher E2 concentrations resulting in a stronger effect. Including the E2 effect on the SHBG synthesis in the model led to a better description of the PK of LNG and in particular of the fluctuations in the LNG and SHBG concentrations.
Conclusions: The PK of LNG was well described by the population PK model where the interaction of LNG and SHBG was considered and additionally a stimulating effect of E2 on the synthesis of SHBG was assumed. Comparison of individual prediction and observations showed that the effect of changes in endogenous E2 concentrations might explain a considerable part of the fluctuations in the SHBG and, indirectly, LNG concentrations.
References:
[1] Dowsett M, Attree S, Virdee S, Jeffcoate S. Oestrogen-related changes in sex hormone binding globulin levels during normal and gonadotrophin-stimulated menstrual cycles. Clinical Endocrinology (1985), 23, 303-312.
Reference: PAGE 25 (2016) Abstr 5883 [www.page-meeting.org/?abstract=5883]
Poster: Drug/Disease modeling - Other topics