A Phase 3, Randomized Double-Blind Study of the Efficacy and Safety of Low-Dose SHP465 Mixed Amphetamine Salts Extended-Release in Children with Attention-Deficit/Hyperactivity Disorder

Mattingly, Greg; Arnold, Valerie; Yan, Brian; Yu, Mingwei; Robertson, Brigitte

doi:10.1089/cap.2020.0005

Cited by 2 publications

(8 citation statements)

References 21 publications

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“…In this study, children treated with SHP465 MAS 6.25-mg doses took less time to fall asleep and remained asleep at night for a longer period with fewer awakenings at FoTA compared with baseline, indicating improved sleep patterns with treatment. There were no substantive changes in other sleep-related parameters, including bedtime resistance, parasomnias, sleep anxiety, and length of time awake per night between baseline and FoTA as measured by the PSQ and CSHQ (no statistical comparisons for any measurements were performed), consistent with previous results with SHP465 6.25 mg in children (aged 6-12 years) and with the SHP465 MAS dose range of 12.5-25 mg in adults [8,12].…”

Section: Discussionsupporting

confidence: 89%

“…Between individual-variability of plasma d-amphetamine and l-amphetamine steady-state exposures (C max and AUC tau,ss ) was low to moderate with a geometric mean CV value range of 29.8−34.7%. A dose of SHP465 MAS 6.25 mg was generally well tolerated, with the general safety and tolerability profiles being consistent with previous observations for SHP465 MAS in children and adolescents [11,12]. The data from this study show that 28-day administration of SHP465 MAS 6.25 mg was well tolerated by children aged 4-5 years and warrants further studies to explore its effectiveness in reducing ADHD symptoms in this age group.…”

Section: Discussionsupporting

confidence: 86%

“…Thereafter, the plasma d-amphetamine and l-amphetamine concentrations declined monoexponentially, with geometric mean terminal half-life values of 10.4 h for d-amphetamine and 12.3 h for l-amphetamine. A dose of SHP465 MAS 6.25 mg was well tolerated in this study, with no serious or severe adverse events reported, similar to the study in children aged 6-12 years treated with the same dose [12]. Although the enzymes involved in amphetamine metabolism are poorly defined, in the liver, amphetamine is metabolized to benzoic acid and hippuric acid, and by CYP2D6 to the active metabolite 4-hydroxy-amphetamine [20,21].…”

Section: Discussionsupporting

confidence: 76%

“…In phase III studies, SHP465 MAS has been shown to significantly improve ADHD symptoms in children, adolescents, and adults with ADHD, with a safety and tolerability profile consistent with amphetamine treatment [8][9][10][11]. In response to a pediatric written request from the [12].…”

Section: Discussionmentioning

confidence: 99%

“…significantly greater reductions in ADHD Rating Scale (ADHD-RS) scores than placebo in adults, adolescents, and children diagnosed with ADHD [8][9][10][11]. Based on data from two randomized, placebo-controlled, phase III clinical studies, SHP465 was well tolerated [11,12] and in one study demonstrated superiority over placebo in reducing ADHD symptoms in children (aged 6-12 years) and adolescents [11]. Although doses between 12.5 and 25 mg once daily (QD) were superior to placebo, a lower dose of 6.25 mg QD failed to reduce ADHD symptoms in this population [11,12].…”

mentioning

confidence: 99%

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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

Ilic

Kugler²,

Yan

et al. 2021

CNS Drugs

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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 treatmentemergent 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. B...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 86%