Vyvanse Mechanism of Action: The Full Pharmacological Pathway From Prodrug to Dopamine Release

Step 1: The capsule carries an inactive prodrug

Lisdexamfetamine dimesylate is a prodrug of amphetamine. The label states that the parent drug is inactive and, in vitro, does not bind norepinephrine or dopamine reuptake sites [1].

Absorption work in rats and in cell cultures found that intact lisdexamfetamine crosses the small intestine by a carrier, probably the peptide transporter PEPT1, with concentrations in portal blood about 10-fold higher than in systemic blood; absorption occurred from the small intestine but not the colon [2]. In blood, unchanged lisdexamfetamine has a plasma half-life averaging under 1 hour [1].

The label's timing data come from children aged 6 to 12 taking a capsule while fasting: lisdexamfetamine peaked at about 1 hour and dextroamphetamine at about 3.5 hours, and food moved the dextroamphetamine peak about 1 hour later without changing total exposure (AUC) or peak concentration (Cmax) [1].

Step 2: Red blood cells split off the lysine

The conversion happens in blood. A 2010 laboratory study found that lisdexamfetamine metabolism occurred primarily in whole blood and only with red blood cells; the slow hydrolysis seen in liver and kidney homogenates was attributed to residual blood in those tissue preparations [2]. The label states that lisdexamfetamine is converted to dextroamphetamine and l-lysine mainly in blood by red blood cells, not by cytochrome P450 enzymes [1].

Separately, the label states that CYP2D6 inhibitors may increase exposure to dextroamphetamine, the active metabolite, and increase the risk of serotonin syndrome, and that treatment is started at lower doses with monitoring during initiation and after dose increases [1].

Dextroamphetamine's half-life is about 10 to 11.3 hours in healthy adults and 8.6 to 9.5 hours in children aged 6 to 12, with no accumulation at steady state in healthy adults [1].

Step 3: Reuptake blockade and increased release

The label's mechanism statement is compact: amphetamines block reuptake of norepinephrine and dopamine into the presynaptic neuron and increase release of these monoamines into the extraneuronal space [1].

A 2005 review of mechanisms of neurotransmitter release by amphetamines describes two apparent primary mechanisms: catecholamines are redistributed from synaptic vesicles into the cytosol, and transmitter is driven out of the neuron through plasma membrane uptake carriers running in reverse. Uptake inhibition and effects on exocytosis, neurotransmitter synthesis and metabolism may also affect extracellular catecholamine levels [4].

Step 4: What the transporter story leaves out

The label is explicit that the exact mode of therapeutic action in ADHD and binge eating disorder is not known [1]. Transporter reversal and vesicle redistribution describe how amphetamines raise extracellular catecholamines, but the mechanism of the clinical effect itself is not established.

Trace amine-associated receptor 1 (TAAR1) is one reason the transporter-only model is considered incomplete. A 2016 overview of a research symposium concluded that TAAR1 is a dopamine and methamphetamine receptor, interacts with DAT and dopamine D2 receptors, and is essential in modulating addiction-related effects of psychostimulants, which challenges the view that these drugs act solely through the dopamine transporter [5].

How long the effect lasts

The prodrug was built for duration. In a phase III trial of 290 children aged 6 to 12 with ADHD, the investigators described lisdexamfetamine as a therapeutically inactive amphetamine prodrug developed to provide extended duration of effect with reduced potential for abuse, overdose toxicity and drug tampering, with the active d-amphetamine molecule gradually released by rate-limited hydrolysis [6].

The time course was measured directly in a laboratory school study by Wigal and colleagues published in 2009. One hundred seventeen children aged 6 to 12 went through 4 weeks of open-label dose optimization (30, 50 or 70 mg/day), then a randomized, placebo-controlled, two-way crossover phase of 1 week per treatment. On the primary SKAMP deportment measure, and on the attention and PERMP measures, lisdexamfetamine was significantly better than placebo at every postdose time point tested, from 1.5 hours through 13.0 hours (P<.005) [3].

Abuse potential and the prodrug

The boxed warning on Vyvanse is for abuse, misuse and addiction: the drug has a high potential for abuse and misuse, which can lead to a substance use disorder, and misuse or abuse of CNS stimulants can cause overdose and death, with risk increased at higher doses or with unapproved methods of administration such as snorting or injection [1]. The label says being a prodrug does not make the drug non-abusable [1].

In the label's crossover abuse-liability study, 38 people with a history of drug abuse received single doses of lisdexamfetamine 50, 100 or 150 mg, immediate-release d-amphetamine 40 mg, or diethylpropion 200 mg [1]. Lisdexamfetamine 100 mg produced significantly less drug liking than d-amphetamine 40 mg, while lisdexamfetamine 150 mg produced drug liking similar to d-amphetamine 40 mg and diethylpropion 200 mg [1].

The label also reports that intravenous lisdexamfetamine 50 mg produced positive subjective effects greater than placebo but less than intravenous d-amphetamine 20 mg [1].

Heart rate, blood pressure and other peripheral effects

The label reports that CNS stimulants raise blood pressure (mean about 2 to 4 mm Hg) and heart rate (mean about 3 to 6 beats per minute), with larger increases in some patients, and says to monitor blood pressure and pulse during treatment [1]. In the two 12-week binge eating disorder trials, mean pulse rose by 4.41 to 6.31 beats per minute on lisdexamfetamine [7].

The label advises avoiding Vyvanse in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease or other serious cardiac disease, and notes that sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease treated with CNS stimulants at ADHD doses [1]. Before treatment, the label calls for assessing cardiac disease through history, family history of sudden death or ventricular arrhythmia, and physical exam [1].

Elimination and the urinary pH interaction

About 96% of an oral lisdexamfetamine dose is recovered in urine: 42% as amphetamine, 25% as hippuric acid and 2% as intact lisdexamfetamine [1].

Urinary pH changes amphetamine levels. The label states that alkalinizing agents such as sodium bicarbonate increase blood levels and potentiate the action of amphetamine, and that coadministration with urinary alkalinizing agents should be avoided; acidifying agents such as ascorbic acid lower blood levels and efficacy, and the dose is increased based on clinical response [1]. Renal function also caps the dose: the label sets a maximum of 50 mg/day in severe renal impairment (GFR 15 to under 30) and 30 mg/day in end-stage renal disease [1].