Correlation of levetiracetam concentration in peripheral blood mononuclear cells with clinical efficacy: A sensitive monitoring biomarker in patients with epilepsy

Abstract

Therapeutic drug monitoring (TDM) is increasingly recommended in antiepileptic drug (AED) therapy, yet a complex relationship exists between the unbound-drug serum concentration (C u.serum ) as a monitoring biomarker and clinical efficacy. The study was designed to investigate the validity of the intracellular unbounddrug concentration in Peripheral Blood Mononuclear Cells (C u.PBMC ) as a feasible TDM tool in relation to levetiracetam (LEV). Methods: Patients from epilepsy out-patient centre were included in a 4-month descriptive prospective study. Trough serum and PBMC LEV concentrations were monthly determined using HPLC and correlated with clinical features, demographic data, and P-glycoprotein (P-gp) expression. Results: Seventy-patients completed the study with a LEV dose range of 500−3000 mg/day. An absolute range for LEV C u.serum and C u.PBMC was 1.00-26.99 and 0.33-4.43 μg/mL, respectively. Unlike C u.serum , the average four-month LEV C u.PBMC displayed a significant positive correlation with clinical features and P-gp expression; where patients with higher LEV C u.PBMC experienced less number of seizure/month, better cognition and quality of life, and had a more reduction in P-gp expression, but no significant correlation with LEV daily dose was observed. A therapeutic response threshold of ≥ 0.82 μg/mL for LEV C u.PBMC was perceived by using a receiver operating characteristic curve that related the number of seizure/month to the LEV C u.PBMC . The validity of this therapeutic threshold was significant in contrast to LEV Cu.serum. Conclusion:Levetiracetam PBMC concentration is a more sensitive biomarker for LEV efficacy and correlates better with clinical events than C u.serum and could represent a novel tool for more precise LEV monitoring.

Correlation of elevated lamotrigine and levetiracetam serum/plasma levels with toxicity: A long-term retrospective review at an academic medical center

“…Future directions to improve efficacy, safety, and identification of toxicity include the use of pharmacogenetic testing (especially for drug-metabolizing enzymes), tissue/organ sampling, and more detailed biomarker analysis including proteomics. There is ongoing research in these realms for lamotrigine and levetiracetam [ 48 , 50 , 51 ].…”

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine

“…Seizures are proven to be major efflux transporter up-regulators where high glutamate levels produced during seizures activate cytosolic phospholipase A2, resulting in BCRP overexpression (Hartz et al 2019). This notion is supported by several experimental and clinical studies that discovered a significant correlation between seizure severity and efflux transporters level (Kwan et al 2002;Hartz et al 2017;Harby et al 2020). Interestingly, this increase in brain BCRP expression appeared after 1 h of seizures.…”

What Is the Therapeutic Reference Range for Levetiracetam? Grand Round/A Case Study

“…The steady-state trough plasma concentration of LEV is not a perfect reflection of its concentration in the central nervous system because P-glycoprotein expression also plays a role. 21 Moreover, the effective concentration may differ depending on the type of seizure. 22 This partially explains the difficulties in defining a therapeutic interval.…”