The effect of laquinimod, a novel immuno-modulator in development to treat Huntington disease, on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy young women
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Laquinimod is an orally dosed immuno-modulator currently under development for Huntington’s disease (HD). Preclinical findings suggest potential teratogenicity of laquinimod, thus the reproductive ability of females with HD treated with laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with laquinimod (0.6 mg/day) was evaluated.
In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose.
The ratio of geometric means and 90% confidence intervals for AUC0-24 and Cmax of EE and LNG with and without laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event.
The combination of COC and laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.
KeywordsLaquinimod Huntington’s disease Pharmacokinetics Oral contraceptive Drug-drug interaction
The authors thank the principal investigator Irina Remez MD, CRS Clinical Research Services Mönchengladbach GmbH, Mönchengladbach Germany. Sandeep Gopalam, M. Pharmacy (Pharmaceutics); Geetha Range Gowda, B.E (Biotechnology) from Lotus Labs Pvt. Ltd.; and Pippa Loupe PhD (Global Research and Development, Teva Pharmaceutical Industries, Overland Park KS) for assistance with manuscript preparation.
Compliance with ethical standards
Conflict of interest
Authors AE, AZ, DM, VD, OBI and OS are employees of Teva Pharmaceuticals Ltd. who are sponsoring the clinical development of laquinimod for Huntington’s disease. TK was a consultant for Teva Pharmaceutics at the time the study was conducted.
Research involving humans and informed consent
The study was carried out in compliance with the Declaration of Helsinki and International Council on Harmonization (ICH) Good Clinical Practice (E6) Guidelines and applicable national and local laws and regulations. The study was initiated after receiving approval from Independent Ethics Committee (IEC) Ethikkommission der Ärztekammer Nordrhein, Düsseldorf Germany, and from national or local regulations of the competent health authorities. All the subjects gave their written consent for voluntary participation.
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