eight/dose normalised AUC and Cmax 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 eva luated 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 Elvanse Adult.
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).
5.3 Preclinical safety data
Non-clinical abuse liability studies indicate that lisdexamfetamine can produce subjective effects in rats and monkeys that are similar to those of the CNS stimulant dexamfetamine, but that are delayed i |
