LAMOTRIGINE PHARMACOKINETICS ACROSS PREGNANCY AND POSTPARTUM

BACKGROUND: Lamotrigine is used for the maintenance treatment of bipolar disorder. Decreased serial lamotrigine serum concentration to dose ratios in pregnant patients compared to their postpartum values suggest the elimination clearance of lamotrigine increases throughout pregnancy. METHODS: After obtaining IRB-approved written informed consent, three pregnant women with bipolar disorder were admitted to the Clinical Research Unit two to three times during their pregnancies and, when possible, at least once within three months postpartum for pharmacokinetic studies. Blood was obtained before oral administration of the patient’s usual lamotrigine maintenance dose. Fourteen additional blood samples were obtained between 1 and up to 24 hours after drug administration. Plasma drug concentrations were measured by liquid chromatography-tandem mass spectrometry and were modeled with two-compartment pharmacokinetic models using the SAAM II software system. RESULTS: Data were well characterized by a two compartment pharmacokinetic model. Postpartum elimination clearance (ClE/F) and total volume of distribution (VSS/F) were very similar to those reported by Cohen et al. (Clin Pharmacol Ther 1987:42:534-41). In the first 15 ± 4 (mean ± S.D.) weeks of pregnancy ClE/F increased 65 ± 29% while VSS/F increased only 11 ± 7%. By 28 ± 5 weeks of pregnancy ClE/F increased 103 ± 46% while VSS/F increased 38 ± 8%. CONCLUSIONS: The increase in VSS/F throughout pregnancy was only a fraction of the simultaneous increase in ClE/F. Therefore, dosing simulations suggest that dose increases to accommodate the changes in ClE/F throughout pregnancy should be divided into two daily doses to prevent an overshoot in peak concentrations with potentially adverse side effects.