Delayed-Release Dimethyl Fumarate Does Not Adversely Affect the Pharmacokinetics of a Commonly Used Oral Contraceptive: A Drug-Drug Interaction Study

Thursday, June 2, 2016
Exhibit Hall
Bing Zhu, MD, PhD , Biogen, Cambridge, MA
Karin Galil, MD, MPH , Biogen, Cambridge, MA
Ivan Nestorov, PhD , Biogen, Cambridge, MA
Guolin Zhao, PhD , Biogen, Cambridge, MA
Venkata Meka, MD , Biogen, Cambridge, MA
Jeanelle Kam, MD, CPI , Covance Clinical Research Unit, Dallas, TX
Sarah I. Sheikh, MD , Biogen, Cambridge, MA
Jim B Lewin, PharmD , Biogen, Cambridge, MA

Background: As women of childbearing age comprise a large proportion of the multiple sclerosis (MS) population, it is important to study the potential drug-drug interaction between the MS therapy delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) and oral contraceptives.

Objectives: To evaluate the effect of DMF 240 mg twice daily (BID) on the pharmacokinetics of norgestimate/ethinyl estradiol once-daily (QD) in healthy women.

Methods: Forty-six healthy volunteers were enrolled in this randomized, open-label, crossover, drug-drug interaction study. Of the 46 subjects enrolled, 32 completed the study. All subjects received norgestimate/ethinyl estradiol QD in the Lead-in Period; eligible subjects were then randomized 1:1 to one of two treatment sequences. In Sequence 1, subjects received norgestimate/ethinyl estradiol QD and DMF 240 mg BID (norgestimate/ethinyl estradiol+DMF) in Period 1, then norgestimate/ethinyl estradiol QD alone in Period 2. In Sequence 2, these regimens were reversed. Each period was 28 days in duration; DMF was administered only for the first 21 days when applicable. To evaluate the pharmacokinetic profiles of norgestimate (via its primary metabolite, norelgestromin) and ethinyl estradiol, blood samples were collected pre-dose and at multiple time points (up to 24 hours) post-first dose on Day 21 of both treatment periods.

Results: Mean plasma norelgestromin and ethinyl estradiol concentration profiles were superimposable following norgestimate/ethinyl estradiol alone and norgestimate/ethinyl estradiol+DMF treatments. There was no statistically significant effect of DMF on the pharmacokinetic parameters of norelgestromin and ethinyl estradiol, with 90% confidence intervals of geometric mean ratios for AUC0-τ and Cmax contained within the 0.8 to 1.25 range. The median values of plasma progesterone, a pharmacodynamic endpoint, were also comparable for each treatment (norgestimate/ethinyl estradiol alone and norgestimate/ethinyl estradiol+DMF). In addition, the safety profile of concurrent use of norgestimate/ethinyl estradiol and DMF was consistent with that observed for DMF in previous studies.

Conclusions: No impact of DMF on the pharmacokinetics or pharmacodynamics of norgestimate/ethinyl estradiol was observed.

Study Supported by: Biogen