Abstract
Rationale: Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared.Methods: Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg), and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of amphetamine, subjective effects, and vital signs were repeatedly assessed. The pharmacokinetic parameters were determined using compartmental modeling.Results: The increase in plasma concentrations of amphetamine had a 0.6 ± 0.6 h (mean ± SD) longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration, but no differences in maximal concentrations or total exposure (AUC) were found between the two treatments. Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with D-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence) were observed after lisdexamfetamine administration compared with D-amphetamine administration. Lisdexamfetamine and D-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects.Conclusion: The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to D-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as D-amphetamine. The study was registered at ClinicalTrials.gov (NCT02668926).
Highlights
Lisdexamfetamine is an inactive prodrug formulation of D-amphetamine (Krishnan and Stark, 2008; Krishnan et al, 2008; Hutson et al, 2014) that is marketed for the treatment of attention-deficit/hyperactivity disorder (ADHD)
When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al, 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al, 2011) reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine
The increase in plasma amphetamine concentrations had a 0.6 ± 0.6 h longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration (Figure 1, Table 1, and Supplementary Table S1)
Summary
Lisdexamfetamine is an inactive prodrug formulation of D-amphetamine (Krishnan and Stark, 2008; Krishnan et al, 2008; Hutson et al, 2014) that is marketed for the treatment of attention-deficit/hyperactivity disorder (ADHD). The conversion of lisdexamfetamine to D-amphetamine is thought to occur gradually, reportedly resulting in a prolonged pharmacokinetic profile with low peak but sustained plasma amphetamine concentrations (Jasinski and Krishnan, 2009a; Steer et al, 2012) Such a prolonged pharmacokinetic profile is considered to be associated with slower effects on dopamine release, lower euphoric effects, and a possibly lower risk of misuse (Jasinski and Krishnan, 2009a; Heal et al, 2013; Coghill et al, 2014). Based on data from animal studies (Rowley et al, 2012) and limited human data (Jasinski and Krishnan, 2009a), we hypothesized that lisdexamfetamine would have (i) a longer time to Cmax (Tmax) than D-amphetamine, (ii) a lower Cmax than D-amphetamine, (iii) an area under the amphetamine concentration-time curve that is identical to D-amphetamine, (iv) a smaller maximal effect (Emax) and (v) a longer time to Emax (Tmax) than D-amphetamine, and (vi) an area under the observed subjective drug effect-time curve that is identical to D-amphetamine
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