What is the mechanism of action for Vyvanse (lisdexamfetamine)?

Mechanism of Action of Vyvanse (Lisdexamfetamine)

Vyvanse (lisdexamfetamine) is a prodrug that is enzymatically converted to dextroamphetamine in the blood, which then increases synaptic concentrations of dopamine and norepinephrine through reuptake inhibition and enhanced neurotransmitter release. 1, 2

Primary Mechanism

• Lisdexamfetamine itself is therapeutically inactive and must be converted to its active form through hydrolysis 1
• After oral administration, lisdexamfetamine is hydrolyzed to l-lysine (an amino acid) and dextroamphetamine, which is responsible for the drug's therapeutic effects 3
• This conversion occurs primarily through enzymatic processes associated with red blood cells 4

Neuropharmacological Actions

• Dextroamphetamine blocks the reuptake of norepinephrine and dopamine into presynaptic neurons 1
• It increases the release of these monoamines into the extraneuronal space 1
• Specifically, dextroamphetamine:
  • Competitively inhibits the dopamine transporter (DAT) 2
  • Competitively inhibits the norepinephrine transporter (NAT) 2
  • Is taken up into neuronal cells where it acts on vesicular monoamine transporter to promote neurotransmitter release 2

Effects on Brain Function

• By enhancing dopamine and norepinephrine activity, particularly in frontal lobe pathways, the drug improves executive function and attention 5
• These neurotransmitter changes increase the efficiency of prefrontal cortex activity 5
• This mechanism helps optimize executive and attentional function in patients with ADHD 5

Unique Prodrug Properties

• The prodrug design creates a rate-limited enzymatic biotransformation 6
• This results in a gradual release of active dextroamphetamine rather than an immediate spike 3
• The pharmacokinetic profile allows for once-daily dosing with approximately 12 hours of activity 6
• This gradual conversion may contribute to its reduced abuse potential compared to immediate-release amphetamines 3

Pharmacokinetic Considerations

• After oral administration, lisdexamfetamine reaches peak concentration (Tmax) at approximately 1 hour 1
• The active metabolite dextroamphetamine reaches peak concentration at approximately 3.5-4.4 hours post-dose 1
• The conversion to dextroamphetamine occurs primarily in the bloodstream rather than during first-pass metabolism in the liver 4
• The pharmacokinetics show low inter-subject (<25%) and intra-subject (<8%) variability 1

The unique prodrug mechanism of lisdexamfetamine provides clinical advantages including consistent drug delivery, reduced potential for abuse, and extended duration of action compared to immediate-release stimulants 3, 4.