Lisdexamfetamine dimesylate: a guide to its use in attention-deficit hyperactivity disorder
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Lisdexamfetamine dimesylate: a guide to its use in attention-deficit hyperactivity disorder Once-daily lisdexamfetamine dimesylate improved the symptoms of attention-deficit hyperactivity disorder (ADHD) in well designed trials in adult and paediatric (aged 6–12 years) patients. It provided continued effectiveness in adults or children with ADHD for up to 12 months in open-label trials. The tolerability profile of lisdexamfetamine dimesylate is consistent with that of the known effects of amfetamines.
What is the rationale for developing the drug? Attention-deficit hyperactivity disorder (ADHD) manifests as a persistent pattern of inattention, hyperactivity and impulsivity.[1-3] ADHD has an early onset, with symptoms that may persist into adulthood. Stimulant medications have proven efficacy in the management of ADHD, but concerns have been raised about the abuse potential of these drugs. Lisdexamfetamine dimesylate (Vyvanse), a long-acting amfetamine prodrug, has been developed to have similar efficacy to that of currently available extended-release central stimulants, but with a novel mechanism of delivery.[4,5] The prodrug structure of the pharmacologically inactive lisdexamfetamine dimesylate allows gradual release of the stimulant drug dextroamfetamine (d-amfetamine) and prevents mechanical drug tampering.
How does its mechanism of delivery differ? After oral administration, lisdexamfetamine dimesylate is enzymatically converted (primarily by red blood cells) to l-lysine, a naturally occurring essential amino acid, and d-amfetamine, which is responsible for its therapeutic
effect.[4,5] Unlike other medications, lisdexamfetamine dimesylate is rapidly and nearly fully dissolved, but has a long duration of effect that may be dependent on its rate of hydrolysis in the the blood. As red blood cells are abundant in the blood and have a very high capacity for enzymatic conversion of lisdexamfetamine dimesylate, saturation of enzymatic conversion of lisdexamfetamine dimesylate in the blood is unlikely to occur.[4,5] It has been suggested[4,5] that the lack of saturation of this conversion process potentially contributes to the low variability of pharmacokinetic parameters of lisdexamfetamine dimesylate and the consistent delivery of d-amfetamine that has been shown between and within individuals in clinical trials.[6,7]
How does the drug work? Although the precise mechanism of action by which amfetamines improve the symptoms of ADHD remains unknown, they are thought to block the reuptake of norepinephrine (noradrenaline) and dopamine into the presynaptic neuron and increase their availability into the extraneuronal space.[8] The potential for abuse with lisdexamfetamine dimesylate may be lower than that with equivalent doses of d-amfetamine, based on results of abuse liability studies in adults with a history of stimulant abuse.[9,10] In one study, oral lisdexamfetamine dimesylate 100 mg had less ‘likability’ than oral immediate-release d-amfetamine 40 mg (equivalent d-amfetamine doses). There was no significant
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