What are the differences in pharmacokinetics between Vyvanse (lisdexamfetamine) and Adderall (amphetamine and dextroamphetamine) in an adult patient with Attention Deficit Hyperactivity Disorder (ADHD) and normal renal function?

Pharmacokinetic Differences Between Vyvanse and Adderall

Vyvanse (lisdexamfetamine) is a prodrug that requires enzymatic hydrolysis to release active dextroamphetamine gradually, resulting in a smoother, longer duration of action with lower abuse potential compared to Adderall (mixed amphetamine salts), which delivers immediate-release amphetamine that is absorbed directly and reaches peak plasma concentrations more rapidly. 1, 2

Mechanism of Drug Activation

• Vyvanse is therapeutically inactive until metabolized in the body, requiring enzymatic hydrolysis in the gastrointestinal tract to cleave the L-lysine amino acid from dextroamphetamine, creating a rate-limited release mechanism 1, 3
• Adderall contains a mixture of amphetamine salts (75% dextroamphetamine and 25% levoamphetamine) that are pharmacologically active immediately upon absorption, without requiring metabolic conversion 4
• The parent lisdexamfetamine molecule does not bind to norepinephrine or dopamine reuptake sites in vitro, meaning only the released dextroamphetamine produces therapeutic effects 2

Absorption and Onset Characteristics

• Vyvanse demonstrates linear pharmacokinetics at therapeutic doses (30-70 mg), with gradual release of active dextroamphetamine producing a smoother onset of action 3
• The rate-limited hydrolysis of lisdexamfetamine prevents rapid spikes in dextroamphetamine blood levels, even when the medication is crushed, snorted, or injected, fundamentally differentiating it from immediate-release formulations 1, 2
• Adderall XR (extended-release) uses a bead delivery system that provides bimodal release, but the amphetamine is still immediately active once released from the beads 4

Duration of Action

• Vyvanse provides efficacy for a full treatment day, up through and including 6 PM, based on parent ratings in morning, afternoon, and early evening assessments in pediatric trials 3
• The once-daily dosing of Vyvanse improves medication adherence compared to multiple daily doses required with immediate-release Adderall 4
• Adderall immediate-release typically requires dosing 2-3 times daily (5-20 mg three times daily for adults), while Adderall XR provides extended coverage with once-daily dosing 4

Abuse Potential Differences

• In controlled human abuse liability studies, lisdexamfetamine 50-100 mg had significantly lower drug-liking scores compared to equivalent doses of immediate-release dextroamphetamine 40 mg, suggesting reduced abuse potential 1, 3
• Lisdexamfetamine does not produce high dextroamphetamine levels when injected or snorted due to the required enzymatic conversion, making it a feasible option for patients with substance use disorder history 2, 5
• One case report demonstrated successful treatment of ADHD with lisdexamfetamine 40 mg in a patient with methamphetamine use disorder, with decreased cravings for stimulants and no relapse over 2 months 5

Clinical Efficacy Profile

• Both medications achieve 70-80% response rates for ADHD treatment, with comparable efficacy and large effect sizes according to the American College of Obstetricians and Gynecologists 4
• Vyvanse demonstrated significant improvements in ADHD Rating Scale Version IV scores compared to placebo (P < 0.001) in both pediatric and adult populations 3
• Long-term open-label studies of lisdexamfetamine showed >60% improvement from baseline in ADHD-RS-IV scores maintained up to 12 months with good tolerability 3

Dosing Considerations

• Vyvanse is titrated in 10-20 mg increments weekly, starting at 20-30 mg daily, with a maximum approved dose of 70 mg daily for adults 4, 6
• Adderall dosing for adults ranges from 10-50 mg total daily dose, with typical starting doses of 10 mg in the morning and titration by 5 mg weekly 7, 4
• The maximum recommended daily amphetamine dose should not exceed 40-50 mg total for adults, though some patients may require up to 65 mg with clear documentation 4, 6

Common Pitfalls to Avoid

• Never combine Vyvanse and Adderall, as this creates excessive total amphetamine exposure and increases cardiovascular and psychiatric adverse effects risk 6
• Do not assume Vyvanse's prodrug formulation eliminates all abuse potential—it reduces but does not eliminate risk, and monitoring remains essential 1, 2
• Avoid switching between amphetamine formulations without accounting for bioequivalence differences in the conversion process 3
• Both medications require the same cardiovascular monitoring (blood pressure, pulse) and assessment for common stimulant adverse effects including decreased appetite, insomnia, and weight loss 6, 3