Abstract
INTRODUCTION: This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity. METHODS: Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C max) and area under the plasma concentration versus time curve from 0 to infinity (AUC0-∞), were assessed using geometric mean ratios with 90 % CIs. RESULTS: Geometric least squares (LS) means (without versus with LDX) for C max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC0-∞ (ng · h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C max. Parent/metabolite C max and AUC0-∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC0-∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported. CONCLUSIONS: LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.