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Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

From the Harvard Neuroendocrine Unit (A.G.H., E.L.F., K.B.K., K.M.F., S.D.S.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Neurology (A.S.B., X.E.M., J.N.), Rhode Island Hospital, Providence; Department of Neurology (E.G.), Newton Wellesley Hospital; Massachusetts General Hospital (D.B.H.), Boston; and Department of Neurology (S.R., B.A.D., E.B.B.), Brigham & Women’s Hospital, Boston, MA.

Address correspondence and reprint requests to Dr. Andrew G. Herzog, Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 aherzog{at}bidmc.harvard.edu

Objective: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well.

Methods: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC).

Results: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS).

Conclusions: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.

AED = antiepileptic drug; BMI = basal metabolic index; COC = combined oral contraceptive; EIAED = enzyme-inducing antiepileptic drug; IGE = idiopathic generalized epilepsy; LRE = localization-related epilepsy; LTG = lamotrigine; VPA = valproate.

Disclosure: Supported by an investigator-initiated grant from Abbott Laboratories.

Received July 2, 2008. Accepted in final form December 1, 2008.

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				I. Wegner, P. M. Edelbroek, S. Bulk, and D. Lindhout Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives Neurology, October 27, 2009; 73(17): 1388 - 1393. [Abstract] [Full Text] [PDF]