Monitoring levetiracetam concentration in saliva during pregnancy is stable and feasible

Abstract

Aims: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy.

Methods: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy.

Results: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 μg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 μg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007.

Conclusion: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted.

Keywords: levetiracetam; plasma; pregnant women with epilepsy; saliva; therapeutic drug monitoring.

FIGURE 1

Relationship between measured plasma and saliva levetiracetam (LEV) concentrations in paired samples from (A) women with epilepsy, including (B) pregnant and (C) nonpregnant participants. Red lines indicate standard errors. The equation of the black lines refer to Pearson linear regression.

FIGURE 2

The ratio of saliva to plasma levetiracetam concentrations.

FIGURE 3

The Receiver Operating Characteristic (ROC) curve of levetiracetam concentration in saliva. The (A) lower and (B) upper thresholds of the reference level of levetiracetam concentration in saliva.

FIGURE 4

Dose‐normalized concentration in plasma (DNCp) and saliva (DNCs) in the three trimesters of pregnancy and nonpregnant women. (A) shows all saliva and plasma samples collected in pairs, including morning samples and samples taken after intake of levetiracetam; (B) shows only morning (trough steady‐state) saliva and plasma samples collected in pairs.