Evaluation of the Potential Pharmacokinetic Interactions Between Vixotrigine and an Oral Contraceptive

Abstract

Background and objective: Vixotrigine is a voltage- and use-dependent sodium channel blocker in development for neuropathic pain management. This study evaluated the effect of coadministration of vixotrigine (metabolized primarily via uridine diphosphate-glucuronosyltransferases) and an oral contraceptive containing ethinyl estradiol (uridine diphosphate-glucuronosyltransferase inducer) and levonorgestrel on the pharmacokinetics and safety of all three compounds.

Methods: In this phase I, open-label, fixed-sequence, multiple-dose study, 36 healthy women received oral vixotrigine 150 mg three times daily for 6 days and once on day 7. This was followed by a washout period, days 8-11. The oral contraceptive was administered alone on days 12-25 and with vixotrigine 150 mg three times daily on days 26-32. Serial blood samples were collected for pharmacokinetic analysis. Safety was assessed.

Results: The geometric least-squares mean ratios (90% confidence intervals) for the area under the concentration-time curve over 8 h and maximum concentration of vixotrigine co-administered with an oral contraceptive vs vixotrigine alone were 0.85 (0.82-0.89) and 0.91 (0.87-0.96), respectively. The geometric least-squares mean ratios (90% confidence interval) for area under the concentration-time curve over 24 h and maximum concentration of ethinyl estradiol with vixotrigine vs ethinyl estradiol alone were 0.94 (0.91-0.97) and 0.89 (0.84-0.94), respectively; the ratios for levonorgestrel with vixotrigine vs levonorgestrel alone were 1.06 (0.98-1.16) and 1.05 (0.98-1.13), respectively. No adverse events occurring with vixotrigine alone were deemed related to the study drug by the investigators.

Conclusions: Coadministration of vixotrigine and an oral contraceptive containing ethinyl estradiol and levonorgestrel had no clinically relevant effect on exposure of all three compounds.

Trial registration: ClinicalTrials.gov registration number: NCT03324685 (registered 25 October, 2017).

Conflict of interest statement

Yuan Zhao, Beth Tidemann-Miller, Romy Christmann, and Himanshu Naik are employees of and own stock/stock options in Biogen. Mark Versavel was a consultant for Biogen during this study.

Figures

Fig. 1

Study design. h hours, OC oral contraceptive, PK pharmacokinetics, QD once daily, TID three times daily. aVixotrigine 150 mg once in the morning of day 7

Fig. 2

Arithmetic mean (± standard deviation) plasma concentration profiles of a vixotrigine, b metabolite M13, c metabolite M14, and d metabolite M16 when vixotrigine was administered alone and with coadministration of an oral contraceptive (OC)

Fig. 3

Arithmetic mean (± standard deviation) plasma concentration profiles of a ethinyl estradiol and b levonorgestrel when the combination of ethinyl estradiol and levonorgestrel was administered alone and with coadministration of vixotrigine. OC oral contraceptive. Dotted black lines in (a) and (b) indicate the lower limit of quantification for ethinyl estradiol (0.0075 ng/mL) and levonorgestrel (0.15 ng/mL), respectively