Pharmacokinetics of Valproate and Lamotrigine Combined Therapy in Pregnancy and its Effect on the Newborn – A Case Report

Abstract

In a previous paper we found that birth length and weight were inversely related to maternal and umbilical cord levels of valproate (VPA), but not to dose. In a case report we tried to determine, whether it is possible to use this data for prediction of fetal plasma concentrations during pregnancy. A 30-year-old woman (59 kg prior to pregnancy) was treated by a combined therapy of VPA (Orfiril long®, 800 mg/day) and lamotrigine (Lamictal®, 200mg/day) for pseudoabsences. Plasma levels of both drugs were measured at steady-state before, during and after pregnancy and also during the delivery. Levels of VPA were measured by gas chromatography and levels of lamotrigine (LTG) by high performance liquid chromatography. Apparent oral clearance (Cl) was calculated for both drugs: daily dose (mg/kg)/serum concentration (mg/L). Drug levels before the pregnancy were 67.9 mg/L for VPA and 15.2 mg/L for LTG. By the time of delivery both levels have decreased to 32.2 mg/L for VPA and 6 mg/L for LTG in maternal serum. Values measured in umbilical cord were 41.6 mg/L (129% of maternal value) for VPA and 5.9 mg/L for LTG (100% of maternal value). Apparent oral clearance of VPA was increased by 171% (from 0.2 L/24 h to 0.54 L/24 h) and of LTG by 143% (from 0.22 L/24 h to 0.54 L/24 h) at the end of 3rd trimester. The birth length was 43 cm and weight 2.15 kg. The low total values of LTG clearance can be attributed to interaction with VPA. The difference between maternal levels and the levels in umbilical cord can be used for prediction of VPA fetal levels during the 1st trimester = 81 mg/L, which is possibly teratogenic and could explain the low birth length.