Newer antiepileptic drugs in women of child-bearing age : pharmacokinetic studies during pregnancy, breastfeeding, and contraception

Epilepsy is a common neurological disorder, affecting men and women almost equally. It has been estimated that 0.3 to 0.4% of pregnant women have epilepsy. Treating women with antiepileptic drugs (AEDs) during pregnancy is particularly challenging because the potential teratogenic effects of AEDs need to be balanced against the risks associated with uncontrolled seizures, which may be a threat to both the mother and fetus. Good knowledge on the drugs' pharmacokinetics in pregnancy and during lactation is required for an optimal use of AEDs. Pregnancy is known to affect the pharmacokinetics of the older generation AEDs, but the information on pharmacokinetics of the newer AEDs in pregnant and lactating women has been very limited.

The overall aim of the present research project was to investigate the pharmacokinetics during pregnancy, lactation, and contraception of some of the most frequently used of the newer generation AEDs, lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP).

A marked decline in plasma levels of LTG during pregnancy was found. For further investigation of the underlying mechanisms behind this pharmacokinetic alteration a new method (liquid chromatography-mass spectrometry) was developed for quantification of LTG and three of its metabolites. The observed increase in the ratio between LTG and the metabolite 2-N-GLUC in plasma during pregnancy suggests that the decreased plasma LTG levels may be related to an increased metabolism of LTG by glucuronidation.

LTG and TPM were shown to transfer freely over placenta, giving an umbilical cord/maternal plasma level ratio close to one. In contrast, the observations may indicate an active transplacental transport of GBP with accumulation in the fetus, giving an umbilical/maternal plasma ratio close to 2. The elimination of LTG in newborns seemed to be slow, probably due to an undeveloped hepatic glucuronidation capacity. Preliminary observations indicate that newborns have a slightly lower capacity to eliminate GBP than adults, probably due to age-related lower renal capacity. The data suggest that newborns have a good capacity to eliminate TPM.

There is an extensive passage of LTG into breast milk and a comparatively slow elimination of LTG in the newborn, which may result in infant plasma levels reaching concentrations comparable to what is seen during active therapy. However, no adverse effects were noted in the infants. The transfer of GBP and TPM into breast milk is considerable, but plasma levels in the nursed infants were low and no adverse effects observed. LTG plasma levels were reduced by more than 50% during co-medication with oral contraceptives (OC), probably due to an increase in LTG glucuronidation rate. The underlying mechanisms are not known but may be similar to those involved during pregnancy.

In conclusion, our findings provide new information on the pharmacokinetics of three of the newer AEDs in relation to pregnancy and lactation. They also highlight the usefulness of TDM as a tool for identifying pharmacokinetic alterations of clinical relevance, for instance due to physiological changes such as pregnancy, and for identification of unexpected drug-drug interactions such as those between OC and LTG. Such knowledge may contribute to an individualized and safer drug therapy for women treated with those newer AEDs.

List of scientific papers

I. Ohman I, Vitols S, Tomson T (2000). Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia. 41(6): 709-13.
https://pubmed.ncbi.nlm.nih.gov/10840403

II. Sabers A, Ohman I, Christensen J, Tomson T (2003). Oral contraceptives reduce lamotrigine plasma levels. Neurology. 61(4): 570-1.
https://pubmed.ncbi.nlm.nih.gov/12939444

III. Beck O, Ohman I, Nordgren HK (2006). Determination of lamotrigine and its metabolites in human plasma by liquid chromatography-mass spectrometry. Ther Drug Monit. 28(5): 603-7.
https://pubmed.ncbi.nlm.nih.gov/17038873

IV. Öhman I, Beck O, Vitols S, Tomson T (2006). Plasma concentrations of lamotrigine and its 2-N-lamotrigine glucuronide metabolite during pregenacy in women with epilepsy. [Manuscript]

V. Ohman I, Vitols S, Tomson T (2005). Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy? Epilepsia. 46(10): 1621-4.
https://pubmed.ncbi.nlm.nih.gov/16190933

VI. Ohman I, Vitols S, Luef G, Soderfeldt B, Tomson T (2002). Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia. 43(10): 1157-60.
https://pubmed.ncbi.nlm.nih.gov/12366729