Vyvanse (Lisdexamfetamine) Pharmacological Profile
Mechanism of Action
Lisdexamfetamine is a therapeutically inactive prodrug that requires hydrolysis in the blood by red blood cells to release the active d-amphetamine and L-lysine, making it fundamentally different from immediate-release amphetamine formulations. 1, 2
- The prodrug design means lisdexamfetamine itself does not bind to dopamine or norepinephrine reuptake sites; only after conversion to d-amphetamine does it become pharmacologically active 2
- Once converted, d-amphetamine blocks the reuptake of dopamine and norepinephrine into presynaptic neurons and increases the release of these monoamines into the extraneuronal space 2, 3
- The conversion occurs through rate-limited enzymatic hydrolysis predominantly by red blood cells, which creates a delayed and sustained release profile compared to immediate-release formulations 1, 2
- This mechanism effectively prevents alternative routes of administration from bypassing the required metabolic conversion 1
Time of Onset
Lisdexamfetamine reaches peak plasma concentration at approximately 1 hour post-dose, but the active metabolite d-amphetamine peaks significantly later. 2
- Capsule formulation: Lisdexamfetamine Tmax occurs at approximately 1 hour, while d-amphetamine Tmax occurs at 3.5 hours post-dose in pediatric patients (ages 6-12) and 3.8 hours in adults under fasted conditions 2
- Chewable tablet formulation: Lisdexamfetamine Tmax at approximately 1 hour, d-amphetamine Tmax at 4.4 hours post-dose 2
- Food delays the Tmax of d-amphetamine by approximately 1 hour (to 4.7 hours after high-fat meal or 4.2 hours with yogurt) but does not affect overall exposure (AUC or Cmax) 2
Peak Plasma Concentration
The peak plasma concentration (Cmax) of d-amphetamine occurs at 3.5-4.4 hours post-dose depending on formulation, with food causing minimal impact on peak levels. 2
- Lisdexamfetamine plasma concentrations are low and transient, becoming non-quantifiable by 8 hours after administration 2
- The chewable tablet produces approximately 15% lower exposure to lisdexamfetamine compared to capsules, but d-amphetamine exposure (Cmax and AUC) remains similar between formulations 2
- High-fat meals with chewable tablets decrease d-amphetamine exposure by only 5-7%, which is clinically insignificant 2
- The pharmacokinetics are linear between 30-70 mg in pediatric patients and 50-250 mg in adults, with low inter-subject (<25%) and intra-subject (<8%) variability 2
Duration of Action
The plasma elimination half-life of d-amphetamine is 8.6-9.5 hours in pediatric patients and 10-11.3 hours in adults, providing therapeutic effects extending up to 14 hours post-dose. 2, 4
- Lisdexamfetamine itself has a plasma elimination half-life of less than 1 hour in patients ages 6 years and older 2
- The active metabolite d-amphetamine provides the sustained therapeutic effect, with efficacy demonstrated at 14 hours post-dose in adults 4
- There is no accumulation of lisdexamfetamine or d-amphetamine at steady state in healthy adults 2
- Approximately 96% of the oral dose is recovered in urine over 120 hours, with 42% as amphetamine-related compounds, 25% as hippuric acid, and only 2% as intact lisdexamfetamine 2
Clinical Implications
- The delayed Tmax and sustained release profile result in lower peak-to-trough fluctuations compared to immediate-release amphetamine, potentially reducing abuse liability through the oral route 5, 6
- The once-daily dosing is typically administered in the morning due to the extended duration of action 7
- The prodrug mechanism provides consistent therapeutic coverage throughout the day without requiring multiple doses 8, 4