Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs

Epilepsy Res. 2016 May;122:84-90. doi: 10.1016/j.eplepsyres.2016.02.013. Epub 2016 Mar 2.

Abstract

Background: Carbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse.

Material and methods: We have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated.

Results: The maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1-2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1-2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%).

Conclusions: The data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral clearance of carbamazepine significantly.

Keywords: Carbamazepine; Carbamazepine-10,11-epoxide; Delivery; Drug–drug interaction; Epilepsy; Therapeutic drug monitoring.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / blood*
  • Blood Chemical Analysis
  • Carbamazepine / administration & dosage
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Therapy, Combination
  • Epilepsy / blood
  • Epilepsy / drug therapy
  • Female
  • Fetal Blood / chemistry*
  • Humans
  • Pregnancy
  • Pregnancy Complications / blood
  • Pregnancy Complications / drug therapy
  • Retrospective Studies
  • Valproic Acid / administration & dosage
  • Young Adult

Substances

  • Anticonvulsants
  • Carbamazepine
  • Valproic Acid
  • carbamazepine epoxide