Lisdexamfetamine

Lisdexamfetamine is a pharmacologically inactive prodrug. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and hydrolysed primarily by red blood cells to dexamfetamine, which is responsible for the drug’s activity.

Amfetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action of amfetamine in ADHD is not fully established, however it is thought to be due to its ability to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The prodrug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.

Absorption

After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract of healthy adults and children (6 to 12 years) with ADHD, thought to be mediated by the high capacity PEPT1 transporter.

Food does not affect the observed AUC and C_max of dexamfetamine in healthy adults after single-dose oral administration of lisdexamfetamine 70 mg capsules but prolongs T_max by approximately 1 hour (from 3.8 hours at fasted state to 4.7 hours after a high fat meal). After an 8-hour fast, the AUCs for dexamfetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Distribution

In 18 children (6 to 12 years) with ADHD, the T_max of dexamfetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate either 30 mg, 50 mg, or 70 mg administered after an 8-hour overnight fast. The Tmax of lisdexamfetamine dimesylate was approximately 1 hour. Linear pharmacokinetics of dexamfetamine after single-dose oral administration of lisdexamfetamine dimesylate was established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years.

Weight/dose normalised AUC and C_max were 22% and 12% lower, respectively, in adult females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine for 7 days. Weight/dose normalised AUC and C_max values were the same in girls and boys following single doses of 30-70 mg.

There is no accumulation of dexamfetamine at steady state in healthy adults and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for 7 consecutive days.

Biotransformation

Lisdexamfetamine dimesylate is converted to dexamfetamine and l-lysine, which occurs by metabolism in blood primarily due to the hydrolytic activity of red blood cells. Red blood cells have a high capacity for metabolism of lisdexamfetamine as in vitro data demonstrated substantial hydrolysis occurs even at low hematocrit levels. Lisdexamfetamine is not metabolised by cytochrome P450 enzymes.

Amfetamine is oxidised at the 4 position of the benzene ring to form 4-hydroxyamfetamine, or on the side chain α or β carbons to form alpha-hydroxy-amfetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amfetamine are both active and each is subsequently oxidised to form 4-hydroxy-norephedrine. Alpha-hydroxy-amfetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amfetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amfetamine.

Elimination

Following the oral administration of a 70 mg dose of radiolabelled 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 faeces over a period of 120 hours. Of the radioactivity recovered in the urine 42% of the dose was related to amfetamine, 25% to hippuric acid, and 2% intact lisdexamfetamine. 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 studies of lisdexamfetamine dimesylate in volunteers. The half-life of dexamfetamine is 11 hours.

Special populations

The pharmacokinetics of dexamfetamine, as evaluated by clearance, is similar in children (aged 6 to 12) and adolescents (aged 13 to 17) ADHD patients, and healthy adult volunteers after correcting for body weight.

Systemic exposure to dexamfetamine is similar for men and women given the same mg/kg dose.

Formal pharmacokinetic studies for race have not been conducted. There is no evidence of any impact of ethnicity on the pharmacokinetics of lisdexamfetamine.

In a pharmacokinetic study of 40 subjects (8 subjects in each of five renal functional groups: normal, mild impairment, moderate impairment, severe impairment, and end stage renal disease) dexamfetamine clearance was reduced from 0.7 L/hr/kg in normal subjects to 0.4 L/hr/kg in subjects with severe renal impairment (GFR 15 to <30 mL/min1.73m² or CrCl <30 mL/min).

In a study of 47 subjects aged 55 years of age or older amfetamine clearance was approximately 0.7 L/hr/kg for subjects 55 to 74 years of age and 0.55 L/hr/kg for subjects ≥75 years of age. This is slightly reduced compared to younger adults (approximately 1 L/hr/kg for subjects 18 to 45 years of age).

In repeat dose toxicity studies the major findings were changes in behaviour, such as increased activity typical of stimulant administration, with associated reductions in body weight gain, growth measurements and food intake, considered to be a consequence of an exaggerated pharmacological response.

Lisdexamfetamine dimesylate was not genotoxic when tested in vitro in the Ames test and the mouse lymphoma assay or in vivo in the mouse bone marrow micronucleus test. Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed. No evidence of carcinogenicity was found in studies in which d-, l-amfetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats.

Lisdexamfetamine dimesylate had no effect on embryofoetal development or survival when administered orally to pregnant rats at doses up to 40 mg/kg/day, and rabbits at doses up to 120 mg/kg/day.

No adverse effects on nervous system development or reproductive function were observed following repeat dose administration of lisdexamfetamine dimesylate to juvenile rats and dogs.

Amfetamine (d- to l-enantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day.

A number of studies in rodents indicate that prenatal or early postnatal exposure to amfetamine (d- or d,l-) at doses similar to those used clinically can result in long-term neurochemical and behavioural alterations. Reported behavioural effects include learning and memory deficits, altered locomotor activity, and changes in sexual function. Similar studies have not been conducted for lisdexamfetamine.