Therapeutic Drug Monitoring of Lacosamide: Is 10 to 20 mg/L a Suitable Reference Range for Patients With Epilepsy?

OBJECTIVES: The reference range for lacosamide (LCM) has been updated from 1 to 10 mg/L to 10 to 20 mg/L. Historically, LCM range was defined from trough-level measurements, but the newer ranges were obtained from peak-level measurements. The purpose of the study was to evaluate the relationship between LCM plasma levels higher than 10 mg/L and the incidence of adverse effects. METHODS: This was a single-center, retrospective, observational study of adult outpatients with epilepsy who were prescribed LCM and had LCM serum concentrations (LCM-SCs) >10 mg/L on drug-fasting samples, measured from June 2017 to December 2020. RESULTS: A total of 55 LCM-SC samples corresponding to 44 patients (25 women [57%]) were analyzed. The median age was 47 (39-61) years. The median LCM-SC was 13.4 (11.2-17.8) mg/L. Adverse effects were reported in 18 patients (41%). Forty-eight percent (21 of 44) of patients required an LCM dose reduction, with a mean LCM-SC of 16.0 (13.2-18.1) mg/L, whereas, in the remaining patients (23 of 44), LCM dose was not modified, with a mean LCM-SC of 12.2 (10.7-14.2) mg/L ( P = 0.0244). Forty-one percent (18 of 44) of patients reported adverse effects related to LCM, with a mean LCM-SC of 15.6 (12.7-18.4) mg/L, whereas, in the remaining patients (26 of 44), adverse effects did not occur, with a mean LCM-SC of 12.6 (10.7-16.5) mg/L ( P = 0.0495). CONCLUSIONS: The 10 to 20 mg/L reference range clearly increases toxicity in patients treated with LCM. Adjusting the reference range upper limit to 12 mg/L with a routine therapeutic drug monitoring program is suggested, to achieve a reasonable probability of efficacy and decrease toxicity.

Measurement of meropenem concentration in different human biological fluids by ultra-performance liquid chromatography-tandem mass spectrometry.

Meropenem is a broad-spectrum antibiotic, often used for the empirical treatment of infections in critically ill patients with acute kidney injury. Meropenem has clinically insignificant protein binding and, as a carbapenem antibiotic, shows time-dependent bacterial killing, meaning that the unbound or free antibiotic concentration in blood should be maintained above the minimal inhibitory concentration of the pathogen for at least 40 % of the dosing interval. We developed and validated simple chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure plasma, filtrate-dialysate, and urine concentrations of meropenem. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH(TM) (2.1 × 100 mm id, 1.7 µm) reverse-phase C(18) column, with a water/acetonitrile linear gradient containing 0.1 % formic acid at a 0.4-mL/min flow rate. Meropenem and its internal standard (ertapenem) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode. The limits of quantification were 0.27, 0.24, and 1.22 mg/L, and linearity was observed between 0.27-150, 0.24-150, and 1.22-2,000 mg/L for plasma, filtrate-dialysate, and urine samples, respectively. Coefficients of variation and relative biases were less than 13.5 and 8.0 % for all biological fluids. Recovery values were greater than 68.3 %. Evaluation of the matrix effect showed ion suppression for meropenem and ertapenem. No carry-over was observed. The validated methods are useful for both therapeutic drug monitoring and pharmacokinetic studies. It could be applied to daily clinical laboratory practice to measure the concentration of meropenem in plasma, filtrate-dialysate, and urine.