Effects of omeprazole on the pharmacokinetic profiles of lisdexamfetamine dimesylate and extended-release mixed amphetamine salts in adults.
OBJECTIVE
To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant, and mixed amphetamine salts extended-release (MAS XR), alone or with omeprazole, a proton pump inhibitor (PPI).


METHODS
This open-label, randomized, 4-period crossover study enrolled healthy adults (18-45 years). Subjects alternately received single doses of LDX 50 mg and MAS XR 20 mg at 4-day intervals. Following washout, subjects received omeprazole (40 mg/day x 14 days), with alternate single doses of LDX 50 mg or MAS XR 20 mg added on days 7 and 11. Blood samples were collected predose and 0 to 96 hours postdose for pharmacokinetic analysis. Safety assessments included adverse events (AEs).


RESULTS
Overall, 24 subjects were randomized; 21 completed the study. For LDX monotherapy, d-amphetamine mean (SD) exposure was 45.0 (13.97) ng/mL and 713.0 (134.75) ng . h/mL; when coadministered with omeprazole it was 46.3 (9.71) ng/mL and 761.6 (191.13) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 3 hours with and without omeprazole. For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng . h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (>or= 1 hour) Tmax with omeprazole. Both medications had AEs consistent with amphetamine use.


CONCLUSIONS
Total exposure was unaffected by omeprazole for both compounds. However, approximately 50% of subjects receiving MAS XR showed an earlier Tmax while on omeprazole, indicating unpredictable release of active drug by the second bead of MAS XR, most likely related to reduced stomach acid while on a PPI compromising the pulsed delivery of MAS XR. No clear trend was observed for LDX.
Haffey
Mary B
MB
Clinical Pharmacology, Shire Development Inc., Wayne, PA 19087, USA. mhaffey@shire.com
Buckwalter
Mary
M
Zhang
Pinggao
P
Homolka
Robert
R
Martin
Patrick
P
Lasseter
Kenneth C
KC
Ermer
James C
JC
D000328:Adult; D000661:Amphetamine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D003913:Dextroamphetamine / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D054539:Medication Therapy Management; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D055815:Young Adult
D003692:Delayed-Action Preparations; D054328:Proton Pump Inhibitors; D000661:Amphetamine; D009853:Omeprazole; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine