Clinical value of saliva therapeutic drug monitoring of newer antiseizure medications

Introduction

Saliva is a promising option for therapeutic drug monitoring, with studies since the 1970s indicating a good correlation between plasma and saliva levels for early anti-seizure medications, although limited data exist for newer generation drugs.

Objectives

To evaluate the reliability and predictive power of saliva as a minimally invasive surrogate marker of plasma concentration for the routine therapeutic drug monitoring (TDM) of newer anti-seizure medications (ASM).

Methods

We collected blood samples at steady state in patients at least 6 h post-dose, paired with unstimulated saliva samples. We evaluated the correlation between plasma and saliva drug levels and the positive and negative predictive value for plasma values extrapolation from saliva levels. A very low saliva level was defined as below half the plasma lower reference limit.

Results

294 adult patients (53 % male) with a mean age of 40 (SD: 16) were enrolled and 589 paired saliva-plasma samples were quantified. The highest significant correlations between saliva and plasma were observed for zonisamide (R²: 0.92) perampanel (0.91), brivaracetam (0.87), followed by topiramate, lamotrigine, lacosamide (0.76–0.68), and rufinamide, levetiracetam, pregabalin (0.63–0.55). No significant correlation was found for the active mono-hydroxy derivative of oxcarbazepine. Despite a good correlation coefficient, the correlations between saliva and plasma levels were generally loose, resulting in a broad predicted range of plasma levels for a given saliva level. Nonetheless, very low saliva levels exhibited strong specificity in predicting low plasma levels, with 87 % to 100 % accuracy, and when saliva levels fell below the limit of quantification, all corresponding plasma levels were below reference ranges.

Conclusions

This large newer ASM paired plasma-saliva collection allows to precise the potential use of saliva in the management of epilepsy, especially for commonly used ASM such as lamotrigine and levetiracetam. Although they correlate well, extrapolating plasma levels from saliva samples is still an imprecise approximation, making it inadequate for fine dosage adjustments. Yet, a very low saliva level has an appreciable discriminative ability for low plasma level. Unstimulated saliva represents a convenient non-invasive alternative to plasma, to readily identify compliance issues or major drug-drug interactions.