Pharmacokinetics, Safety, and Tolerability of SHP465 Mixed Amphetamine Salts After Administration of Multiple Daily Doses in Children Aged 4–5 Years with Attention-Deficit/Hyperactivity Disorder

BACKGROUND: Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted. OBJECTIVES: We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4–5 years with ADHD. METHODS: In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4–5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (C(max)), plasma trough drug concentration, time to C(max) during a dosing interval (t(max)), area under the concentration–time curve from time 0 to time of last collected sample, area under the concentration–time curve over the dosing interval (24 h) at steady state (AUC(tau,ss)), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t(1/2)), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs. RESULTS: Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m(2), respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median t(max)) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t(1/2) of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, C(max) and AUC(tau,ss) were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant. CONCLUSIONS: In children aged 4–5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03327402 (31 October, 2017).