Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.

Pharmacokinetic Properties

12.3   Pharmacokinetics

Pharmacokinetic studies after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations) and pediatric (6 to 12 years) patients with ADHD (capsule formulation). After single dose administration of lisdexamfetamine dimesylate, pharmacokinetics of dextroamphetamine was found to be linear between 30 mg and 70 mg in a pediatric study (6 to 12 years), and between 50 mg and 250 mg in an adult study. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. There is no accumulation of lisdexamfetamine and dextroamphetamine at steady state in healthy adults.

Absorption

Capsule formulation
Following single-dose oral administration of VYVANSE capsule (30 mg, 50 mg, or 70 mg) in patients ages 6 to 12 years with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 3.5 hours post dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages 6 to 12 years as the adults following single doses of 30 mg to 70 mg VYVANSE capsule.

Effect of food on capsule formulation
Neither food (a high fat meal or yogurt) nor orange juice affects the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of VYVANSE capsules.
Food prolongs Tmax by approximately 1 hour (from 3.8 hours at fasted state to 4.7 hours after a high fat meal or to 4.2 hours with yogurt). After an 8-hour fast, the AUC for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Elimination
Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non- quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in volunteers ages 6 years and older. The plasma elimination half- life of dextroamphetamine was approximately 8.6 to 9.5 hours in pediatric patients 6 to 12 years and 10 to 11.3 hours in healthy adults

Metabolism
Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells after oral administration, lisdexamfetamine.
In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.
Excretion
Following oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine.

Specific Populations
Exposures of dextroamphetamine in specific populations are summarized in Figure 1.

Figure 1: Specific Populations*:



*Figure 1 shows the geometric mean ratios and the 90% confidence limits for C max and AUC of d-amphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55-64 years as the reference.
Drug Interaction Studies
Effects of other drugs on the exposures of dextroamphetamine are summarized in Figure 2.

Figure 2: Effect of Other Drugs on VYVANSE:
The effects of VYVANSE on the exposures of other drugs are summarized in Figure 3.


Figure 3 Effect of VYVANSE on Other Drugs:



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