Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: A novel d-amphetamine pro-drug

• Published in: Neuropharmacology Vol. 87; pp. 41 - 50
• Main Authors: Hutson, Peter H., Pennick, Michael, Secker, Roger
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2014
• Subjects: Animals; Attention-deficit/hyperactivity disorder; Brain - drug effects; Brain - metabolism; Central Nervous System Stimulants - pharmacokinetics; Central Nervous System Stimulants - pharmacology; Central Nervous System Stimulants - toxicity; d-Amphetamine; Dextroamphetamine - pharmacokinetics; Dextroamphetamine - pharmacology; Dextroamphetamine - toxicity; Humans; Lisdexamfetamine Dimesylate; Pharmacokinetics; Pharmacology; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Prodrugs - toxicity; Toxicology; Lisdexamfetamine dimesylate; ADHD; VMAT; d-Amphetamine; CHO; Attention-deficit/hyperactivity disorder; GLY-SAR; LC–MS/MS; Toxicology; t1/2; CYP; PEPT; Cmax; LDX; P-gp; IP; Pharmacology; CCK; IV; ET; LD50; SERT; AT; Papp; DAT; NOAEL; GABA; MAO; Pharmacokinetics; 5-HT; NET; NK
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.02.014

Lisdexamfetamine dimesylate (LDX) is a novel pro-drug of d-amphetamine that is currently used for the treatment of attention-deficit/hyperactivity disorder in children aged ≥6 years and adults. LDX is enzymatically cleaved to form d-amphetamine following contact with red blood cells, which reduces the rate of appearance and magnitude of d-amphetamine concentration in the blood and hence the brain when compared with immediate-release d-amphetamine at equimolar doses. Thus, the increase of striatal dopamine efflux and subsequent increase of locomotor activity following d-amphetamine is less prominent and slower to attain maximal effect following an equimolar dose of LDX. Furthermore, unlike d-amphetamine, the pharmacodynamic effects of LDX are independent of the route of administration underlining the requirement to be hydrolyzed by contact with red blood cells. It is conceivable that these pharmacokinetic and pharmacodynamic differences may impact the psychostimulant properties of LDX in the clinic. This article reviews the preclinical pharmacokinetics, pharmacology, and toxicology of LDX. This article is part of the Special Issue entitled ‘CNS Stimulants’. •Lisdexamfetamine (LDX) is rapidly absorbed after intact oral administration.•The peptide transporter PEPT1 likely mediates absorption in the small intestine.•Red blood cell peptidase(s) metabolize LDX into d-amphetamine and its metabolites.•CYP enzymes do not metabolize LDX and LDX does not cross the blood–brain barrier.•LDX has a blunted effect on brain dopamine function versus other stimulant drugs.