81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

Study ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

10 Pharmacodynamics and Tolerability of Intranasally Administered Immediate-Release Amphetamine Sulfate Among Recreational Intranasal StimulantUsers

Study ObjectiveDespite increased nonmedical use of ADHD prescription stimulants, there are limited data to inform selection of intranasal doses for abuse-potential evaluations. This study determined a dose of amphetamine sulfate that is tolerable and distinguishable from placebo on pharmacodynamic (PD) measures.MethodsIn this randomized, double-blind, placebo-controlled, dose-escalation study, healthy, nondependent, recreational stimulant users received a single intranasal dose of amphetamine sulfate (20, 30, or 40mg ; n=6 per group) or placebo (n=2 per group). PD and safety were assessed pre-dose and ≤24hours post-dose. Drug Liking was measured using a bipolar Visual Analogue Scale (VAS; 0–100). Dose selection criteria were complete dose insufflation (≥95%); demonstration of peak Drug Liking ≥75 points, and ≥15 points greater than placebo in ≥3 participants receiving active drug; and tolerability.ResultsPeak Drug Liking criteria were met in the 20-, 30-, and 40-mg groups by 2, 0, and 6 participants, respectively. Mean (SD) peak Drug Liking was 62 (13.0), 71 (17.8), and 93 (8.7) for amphetamine sulfate versus 54 (3.5), 76 (34.6), and 51 (0) for placebo in the 20-, 30-, and 40-mg groups, respectively. Thirteen participants experienced mild AEs (n=1, 4, 6, and 1 in 20-, 30-, 40-mg, and placebo groups, respectively), there were no serious or clinically significant AEs. The most common AE was nostril burning sensation (active drug, n=7). There were no instances of an incompletely insufflateddose.ConclusionA 40-mg intranasal dose produced distinguishable PD effects and was well tolerated. This dose has been selected for further abuse-potential evaluations.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.