Pheochromocytoma (PhC) and Paraganglioma (PG) are rare neuroendocrine tumors characterized by uncontrolled catecholamine secretion. Although rare, much attention is still devoted to identifying a unique biochemical signature of these diseases to reduce false positives, thus improving patient outcomes, and customizing clinical laboratory practices to available resources and specific diagnostic needs. Emerging knowledge into catecholamine metabolism has greatly improved diagnostic strategies, with current international guidelines recognizing plasma free or urinary fractionated metanephrine measurements as the recommended first-line biochemical tests. This narrative review highlights the clinical utility of measuring plasma free metanephrines compared to urinary catecholamines in the diagnosis of these conditions. Plasma free metanephrines offer superior sensitivity and specificity compared to catecholamines due to their continuous secretion, which is independent from tumor size and catecholamine fluctuations. This review also addresses preanalytical and methodological challenges, emphasizing patient preparation, sample stability and advanced analytical techniques currently available. Methodologies such as LC-MS/MS have demonstrated improved diagnostic accuracy compared to traditional immunoassays, offering enhanced analytical performance in terms of sensitivity, specificity, and reduced susceptibility to interferences.

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved for the treatment of drug-resistant focal epilepsy in adults. Notwithstanding significant proof of efficacy, real-world pharmacokinetics (PK) data are lacking, particularly regarding sex-based variations and the effect of concomitant ASMs. This exploratory study aimed to investigate the PK profile of CNB in responder adults with drug-resistant focal epilepsy and assess potential relationship with concomitant ASMs and clinical variables. Methods: We enrolled 17 patients receiving add-on CNB. The concentration-to-dose ratio (C/D), incremental slope (ΔC/ΔD), and dose-to-concentration AUC were calculated. Enrolled individuals were stratified into three exposure clusters (low, medium, and high). Univariate ANOVA was used to explore associations between PK parameters, clinical variables and concomitant ASMs. Results: Sex appeared to be associated with AUC cluster classification (p = 0.026), showing females predominating in the high-exposure group. A nonlinear dose-concentration relationship emerged from the ΔC/ΔD analysis, showing steeper slopes at low doses (12.5–50 mg), great variability at higher doses (100–200 mg), and a negative slope in some individuals. Higher CNB concentrations were observed in patients co-treated with lacosamide, while concomitant topiramate was associated with lower exposure. Carbamazepine and valproate showed non-significant trends consistent with their known enzyme-inducing and inhibiting properties. Conclusions: PK of CNB appears highly variable and seems to be influenced by sex and concomitant ASMs. These findings highlight the importance of therapeutic drug monitoring and individualized titration strategies to optimize efficacy and safety in clinical practice. These results should be regarded as exploratory and hypothesis-generating due to the small and monocentric sample size and need to be confirmed in larger, multicenter cohorts.