Published: 7 March 2024

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Pharmacokinetic changes in pregnancy and effects on antiepileptic medicine plasma levels

Published 7 March 2024
Prescriber Update 45(1): 12–14
March 2024

This article provides an overview of the pharmacokinetic changes in pregnancy, their effects on antiepileptic medicine (AEM) plasma levels, and therapeutic drug monitoring considerations. Due to the risks to the fetus, as well as the potential need to monitor medicine levels, all pregnancies should be planned.

Pharmacokinetic changes during pregnancy

Physiological changes during pregnancy can affect the absorption, distribution, metabolism and elimination of medicines. This may influence the plasma levels of AEMs during pregnancy.¹

Absorption

During pregnancy, the gastric pH increases (becomes less acidic) while gastric emptying and intestinal motility decreases.¹ For most medicines, there is no significant clinical effect as a result of these changes.²

Distribution

The plasma volume and total body water increases during pregnancy. This in turn can lower the plasma concentration of hydrophilic medicines.³

Plasma protein concentrations also fall during pregnancy, which can result in decreased plasma protein binding of medicines. For example, albumin concentrations decrease on average by 1% at 8 weeks gestation, 10% at 20 weeks, and 13% at 32 weeks³. The total plasma concentration of highly protein bound medicines may decrease in parallel with albumin levels.¹

Metabolism

The activity of enzymes involved in drug metabolism may change during pregnancy. Certain cytochrome P450 (CYP450) enzyme activities may increase (eg, CYP3A4 and CYP2D6) or decrease (eg, CYP2C19) and uridine glucuronyl transferase (UGT) enzyme activity increases. Therefore, the plasma levels of a medicine may increase or decrease during pregnancy, depending on the hepatic enzymatic process involved in its metabolism.²  

Excretion

Blood flow and glomerular filtration rate (GFR) increase during pregnancy, leading to increased renal clearance.¹ For medicines that are primarily renally cleared, renal clearance is expected to parallel changes in GFR.³

Plasma levels of antiepileptic medicines may change during pregnancy

Pregnancy may reduce maternal AEM plasma levels. This reduction varies depending on the type of AEM and between individuals.¹ A projected decrease in serum concentration for some AEMs (if no dose changes are made) and possible pharmacokinetic mechanisms described in the literature are outlined in Table 1.

Table 1: Projected changes in serum concentrations of selected antiepileptic medicines during pregnancy (if no dose changes are made) and possible mechanisms

Antiepileptic medicine	Decrease in serum concentrationa	Examples of possible pharmacokinetic mechanisms described in the literature (list not exhaustive)
Phenobarbital	Up to 55%	Altered protein bindingb
Phenytoin	60 to 70%	Altered protein bindingc
Carbamazepine	0 to 12%	Not well describedd
Oxcarbazepine monohydrate-derivative	36 to 62%	Enhanced hepatic metabolismd Increased renal clearanced
Sodium valproate	Up to 23%	Altered protein bindingc
Lamotrigine	69% decrease in 77% of populatione 17% decrease in 23% of populatione	Uridine glucuronyl transferase enzyme upregulationd Increased renal clearanced
Gabapentin and pregabalin	Insufficient data	Increased renal clearanced
Topiramate	Up to 30%	Increased renal clearanced
Levetiracetam	40 to 60%	Increased renal clearanced
Zonisamide	Up to 35% but little data	Reduced gastrointestinal absorptiond Enhanced hepatic metabolismd Increased renal clearanced

Notes:

1. Adpated from McElrath T and Gerard E. 2023. Management of epilepsy during preconception, pregnancy, and the postpartum period. In: UpToDate 23 October 2023. URL: www.uptodate.com/contents/management-of-epilepsy-during-preconception-pregnancy-and-the-postpartum-period (accessed 10 January 2024).
2. Yerby MS, Friel PN, McCormick K, et al. 1990. Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding. Epilepsy Research 5(3): 223-8. DOI: 10.1016/0920-1211(90)90042-t (accessed 10 January 2024).
3. Brodtkorb E and Reimers A. 2008. Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy. Seizure 17(2): 160-5. DOI: https://doi.org/10.1016/j.seizure.2007.11.015 (accessed 10 January 2024).
4. Arfman IJ, Wammes-van der Heijden EA, Ter Horst PGJ, et al. 2020. Therapeutic drug monitoring of antiepileptic drugs in women with epilepsy before, during, and after pregnancy. Clinical Pharmacokinetics 59(4): 427-45. DOI: 10.1007/s40262-019-00845-2 (accessed 10 January 2024).
5. A pharmacokinetic analysis utilising a population-based model demonstrated two subpopulations based on the rate of lamotrigine clearance during pregnancy. Most women (77 percent) displayed a marked increase in lamotrigine clearance (ie, a decrease in serum concentration) from baseline, whereas a minority (23 percent) had a minimal decrease (Source: McElrath and Gerard, see note a above).

Considerations for therapeutic drug monitoring in pregnancy

The relationship between changes to plasma AEM levels in pregnancy and deterioration in seizure control is not well characterised, and pregnant patients may remain seizure free despite lower AEM levels. However, therapeutic drug monitoring may be useful in some cases and dose adjustments may be needed.¹ Seek specialist advice.

The New Zealand Formulary recommends dose adjustments during pregnancy based on therapeutic drug monitoring for phenytoin, carbamazepine and lamotrigine.⁴ The dose of levetiracetam may need to be increased in the second and third trimesters.⁴ Carefully monitor the dose of other AEMs during pregnancy and adjust if clinically needed.⁴

To aid clinical decision making during pregnancy, it may be useful to establish baseline AEM plasma levels as part of pregnancy planning.^5,6 This level may then be used to compare and titrate against when AEMs levels are measured during pregnancy.⁷

The optimal frequency for therapeutic drug monitoring of AEMs during pregnancy is unknown.⁵ Some guidelines recommend monitoring every trimester or more frequently if seizures occur.⁸

Additional information

For prescribers

• Refer to the medicine data sheet and local clinical guidance.

For patients

• Refer to the consumer medicine information or package leaflet for your medicine.
• See also Medsafe’s Epilepsy medicines and pregnancy consumer information leaflet – available in English (PDF, 2 pages, 271 KB) and te reo Māori (PDF, 2 pages, 569 KB).

References

1. Tomson T, Landmark CJ and Battino D. 2013. Antiepileptic drug treatment in pregnancy: Changes in drug disposition and their clinical implications. Epilepsia 54(3): 405-14. DOI: https://doi.org/10.1111/epi.12109 (accessed 8 January 2024).
2. Blackburn S. 2012. Pharmacokinetic changes in the pregnant woman. The Journal of Perinatal & Neonatal Nursing 26(1): 13-14. DOI: 10.1097/JPN.0b013e318242fdf1 (accessed 8 January 2024).
3. Feghali M, Venkataramanan R and Caritis S. 2015. Pharmacokinetics of drugs in pregnancy. Seminars in Perinatology 39(7): 512-19. DOI: 10.1053/j.semperi.2015.08.003 (accessed 8 January 2024).
4. New Zealand Formulary (NZF). 2024. NZF v139: Antiepileptic drugs 1 January 2024. URL: nzf.org.nz/nzf_2599 (accessed 17 January 2024).
5. McElrath T and Gerard E. 2023. Management of epilepsy during preconception, pregnancy, and the postpartum period. In: UpToDate 23 October 2023. URL: www.uptodate.com/contents/management-of-epilepsy-during-preconception-pregnancy-and-the-postpartum-period (accessed 10 January 2024).
6. Arfman IJ, Wammes-van der Heijden EA, Ter Horst PGJ, et al. 2020. Therapeutic drug monitoring of antiepileptic drugs in women with epilepsy before, during, and after pregnancy. Clinical Pharmacokinetics 59(4): 427-45. DOI: 10.1007/s40262-019-00845-2 (accessed 10 January 2024).
7. National Institute for Health and Care Excellence (NICE). 2022. Epilepsies in children, young people and adults: Support and monitoring for women planning pregnancy or who are pregnant. NICE Guideline [NG217] 22 April 2022. URL: www.nice.org.uk/guidance/ng217/chapter/rationale-and-impact#support-and-monitoring-for-women-planning-pregnancy-or-who-are-pregnant-2 (accessed 25 January 2024).
8. Richards N, Reith D, Stitely M, et al. 2018. Are doses of lamotrigine or levetiracetam adjusted during pregnancy? Epilepsia Open 3(1): 86-90. DOI: 10.1002/epi4.12086 (accessed 10 January 2024).