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Lisdexamfetamine (LDX) is a long-acting prodrug stimulant indicated for the treatment of attention-deficit/hyperactivity disorder and binge-eating disorder symptoms. In vivo hydrolysis of LDX amide bond releases the therapeutically active d-amphetamine (d-AMPH). Since toxicological tests in biological samples can detect AMPH from the use of some legal medications, efficient methods are needed in order to correctly interpret the results. The aim of this study was to develop and validate an LC-MS/MS method for the simultaneous quantification of LDX and its main biotransformation product AMPH in human oral fluid, plasma and urine. Calibration curve range for both analytes was 1-128 ng/mL in oral fluid and plasma and 4-256 ng/mL in urine, being the lowest concentration the limit of quantification. Accuracy of the determined values of the target analytes for the five control levels ranged from 94.8 to 111.7% for oral fluid, from 91.3 to 100.2% for plasma and from 94.8 to 109.8% for urine. Imprecision for the five control levels did not exceeded 12.8% for oral fluid, 16.2% for plasma and 17.1% for urine. The method developed for the three matrices was validated and was also successfully applied to assess real samples, showing for the first time the detection of LDX in oral fluid.

Lisdexamfetamine (LDX) is a long‐acting prodrug stimulant indicated for the treatment of attention‐deficit/hyperactivity disorder (ADHD) and binge‐eating disorder (BED) symptoms. In vivo hydrolysis of the LDX amide bond releases the therapeutically active d‐amphetamine (d‐AMPH). This study aims to describe the pharmacokinetics of LDX and its major metabolite d‐AMPH in human oral fluid, urine and plasma after a single 70 mg oral dose of LDX dimesylate. Six volunteers participated in the study. Oral fluid and blood samples were collected for up to 72 h and urine for up to 120 h post‐drug administration for the pharmacokinetic evaluation of intact LDX and d‐AMPH. Samples were analyzed by LC‐MS/MS. Regarding noncompartmental analysis, d‐AMPH reached the maximum concentration at 3.8 and 4 h post‐administration in plasma and oral fluid, respectively, with a mean peak concentration value almost six‐fold higher in oral fluid. LDX reached maximum concentration at 1.2 and 1.8 h post‐administration in plasma and oral fluid, respectively, with a mean peak concentration value almost three‐fold higher in plasma. Intact LDX and d‐AMPH were detected in the three matrices. The best fit of compartmental analysis was found in the one‐compartment model for both analytes in plasma and oral fluid. There was a correlation between oral fluid and plasma d‐AMPH concentrations and between parent to metabolite concentration ratios over time in plasma as well as in oral fluid.

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