Abstract
The purpose of this work was to assess the pharmacokinetics and safety of lisdexamfetamine dimesylate (LDX) delivered and released regionally in the gastrointestinal (GI) tract. In this open-label, randomized, crossover study, oral capsules and InteliSite delivery capsules containing LDX (50 mg) with radioactive marker were delivered to the proximal small bowel (PSB), distal SB (DSB), and ascending colon (AC) during separate periods. Gamma scintigraphy evaluated regional delivery and GI transit. LDX and d-amphetamine in blood were measured postdose (≤72 h). Treatment-emergent adverse events (TEAEs) were assessed. Healthy males (n = 18; 18–48 years) were enrolled. Mean (S.D.) maximal plasma concentration (Cmax) was 37.6 (4.54), 40.5 (4.95), 38.7 (6.46), and 25.7 (9.07) ng/ml; area under the concentration-time curve to the last measurable time point was 719.1 (157.05), 771.2 (152.88), 752.4 (163.38), and 574.3 (220.65) ng · h · ml−1, respectively, for d-amphetamine after oral, PSB, DSB, and AC delivery of LDX. Median time to Cmax was 5, 4, 5, and 8 h, respectively. Most TEAEs were mild to moderate. No clinically meaningful changes were observed (laboratory, physical examination, or electrocardiogram). LDX oral administration or targeted delivery to small intestine had similar d-amphetamine systemic exposure, indicating good absorption, and had reduced absorption after colonic delivery. The safety profile was consistent with other LDX studies.
Footnotes
This work was supported by Shire Development Inc., which provided funding to SCI Scientific Communications & Information for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Drug Metabolism and Disposition were made by the authors independently.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- GI
- gastrointestinal
- ICC
- InteliSite Companion Capsules
- ADHD
- attention-deficit/hyperactivity disorder
- LDX
- lisdexamfetamine dimesylate
- PEPT1
- peptide cotransporter 1
- PSB
- proximal small bowel
- DSB
- distal small bowel
- AC
- ascending colon
- IN
- intranasal
- 111In
- Indium-111
- 99mTc-DTPA
- technetium-99m-diethylenetriamine-pentaacetic acid
- QC
- quality control
- AE
- adverse event
- TEAE
- treatment-emergent adverse event
- Cmax
- maximal observed plasma concentration
- Tmax
- time to Cmax
- t1/2
- apparent terminal half-life
- ATC
- postdose arrival time
- AUC
- area under the curve
- AUC0-inf
- AUC from time zero to infinity
- AUCDSI
- small intestine (distal only) gastrointestinal transit curve
- AUClast
- area under the plasma concentration-time curve to the last measurable time point
- AUCSI
- AUC of small intestine gastrointestinal transit curve
- CI
- confidence interval
- SITT
- small intestine transit time.
- Received June 9, 2011.
- Accepted October 28, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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