Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers

• Published in: Clinical therapeutics 2010-09, Vol.32 (10), p.1813-1821
• Main Authors: Stockis, Armel, PhD, Sargentini-Maier, Maria Laura, PhD, Otoul, Christian, BioEng, Connor, Alyson, PhD, Wilding, Ian, PhD, Wray, Heather, MD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anticonvulsants - administration & dosage; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; Bioavailability; Biological and medical sciences; Biological Availability; Capsules; Colon; Colon, Ascending - diagnostic imaging; Colon, Ascending - metabolism; Cross-Over Studies; Drug Delivery Systems - methods; Drug dosages; Electromagnetic Fields; Enterion; Epilepsy; Gastrointestinal Transit; Humans; Internal Medicine; Intestinal Absorption; Intestine, Small - diagnostic imaging; Intestine, Small - metabolism; levetiracetam; Male; Medical Education; Medical sciences; Middle Aged; Pharmaceuticals; Pharmacokinetics; Pharmacology. Drug treatments; Piracetam - administration & dosage; Piracetam - analogs & derivatives; Piracetam - blood; Piracetam - pharmacokinetics; Radionuclide Imaging; Small intestine; Tablets; Technetium Tc 99m Pentetate; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.09.001

Abstract Background: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. Objective: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. Methods: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters Cmax , Tmax , AUC0−last , AUC0−∞ and t½ were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. Results: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC0−last values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) μg · h/mL, respectively. Values for bioavailability in the proxim