Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use.
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.
Herzog
A G
AG
Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. aherzog@bidmc.harvard.edu
Blum
A S
AS
Farina
E L
EL
Maestri
X E
XE
Newman
J
J
Garcia
E
E
Krishnamurthy
K B
KB
Hoch
D B
DB
Replansky
S
S
Fowler
K M
KM
Smithson
S D
SD
Dworetzky
B A
BA
Bromfield
E B
EB
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D015992:Body Mass Index; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects*; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy / Q000523:psychology; D005260:Female; D005498:Follicular Phase / Q000378:metabolism; D006801:Humans; D000077213:Lamotrigine; D008183:Luteal Phase / Q000378:metabolism; D008597:Menstrual Cycle / Q000378:metabolism*; D008875:Middle Aged; D014227:Triazines / Q000493:pharmacokinetics*; D014635:Valproic Acid / Q000493:pharmacokinetics*; D055815:Young Adult
D000927:Anticonvulsants; D003277:Contraceptives, Oral, Combined; D014227:Triazines; D014635:Valproic Acid; D000077213:Lamotrigine