Regional gastrointestinal delivery of remogliflozin etabonate in humans.

Remogliflozin etabonate (RE) is the prodrug of remogliflozin (R), an inhibitor of renal glucose transport designed to reduce blood glucose concentrations for the treatment of type 2 diabetes. This open-label, randomized, single-dose, four-way crossover study, (with one add-on arm) in eight healthy men evaluated the regional gastrointestinal absorption of RE, the systemic appearance of the active entity R, and an active metabolite, GSK279782. The InteliSite(®) Companion Capsule was used to administer a single dose of RE 100 mg to the mid-small intestine or cecum/colon. Oral administration of the IR tablet of RE showed similar bioavailability of R compared with small intestine delivery with both suspension and solution. The lowest bioavailability of remogliflozin was found with large intestine delivery and therefore not a suitable region for prodrug delivery. Although both lower permeability and decreased ester hydrolysis of remogliflozin etabonate in the colon can explain reduced plasma exposures of remogliflozin, the data suggest relatively limited remogliflozin etabonate hydrolysis in the colon and provides evidence for a diminishing gradient of esterase activity from small to large intestine.

Pharmacokinetics of lisdexamfetamine dimesylate after targeted gastrointestinal release or oral administration in healthy adults.

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 (C(max)) 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 C(max) 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.

A single-dose, open-label, randomized, scintigraphic study to investigate the gastrointestinal behavior of 2 triple-combination cold products (acetaminophen, phenylephrine, and dextromethorphan) in healthy male volunteers.

BACKGROUND: Common cold symptoms may be mitigated by products in caplet, nasal spray, and oral solution formulations, although variations exist in the bioavailability of the active ingredients contained within these products. Rapid gastric emptying (GE) of these active ingredients is important for reducing the delay between drug absorption and onset of cold symptom relief. Hot drink cold remedies are associated with greater comfort and may enhance the bioavailability of active ingredients. The objective of this study was to characterize the gastrointestinal transit of powder (reconstituted in hot water) and caplet formulations of commercially available multisymptom cold medications. METHODS: This was an open-label, single-dose, parallel-group study. Healthy male adults under fasted conditions were randomized 1:1 to receive a single dose of radiolabeled Theraflu Daytime Severe Cold and Cough powder for oral solution or radiolabeled Theraflu ExpressMax Daytime Severe Cold and Cough caplet. External gamma scintigraphy was utilized to monitor GE and intestinal transit of two radiolabeled drug formulations. RESULTS: A total of 28 participants completed the study. The mean ± SE GE onset times were 1.1 ± 0.3 min and 8.5 ± 1.8 min for powder and caplet formulations, respectively. The mean ± SE GE completion times were 121 ± 13 min and 65 ± 13 min, respectively. Despite the similar mean times to GE25%, the powder had later mean GE50% (23 ± 3.0 vs 16 ± 3.2 min, respectively) and GE90% (85 ± 12 vs 36 ± 9 min, respectively) than caplets. Caplets had a shorter overall GE half-life, lower total gastric exposure, and faster transit time through the small intestine versus the powder formulation. No serious safety events were observed. CONCLUSION: The results of this study in healthy male adults suggest that the Theraflu powder formulation had a more rapid GE onset but longer time to GE completion than the caplet formulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03415243.

Vaginal distribution of Replens and K-Y Jelly using three imaging techniques.

BACKGROUND: Determination of vaginal distribution is important to the development of potential vaginal microbicidal or spermicidal products. STUDY DESIGN: This was a descriptive study of three imaging techniques with a randomized crossover assignment of two gels and activity status within each technique. METHOD: Each of three sites utilized one technique. Three nulligravid women and three parous women were to be enrolled at each site. We studied the effects of time, ambulation, parity and body mass index on vaginal spreading of two commonly used gels, K-Y Jelly and Replens. Imaging by magnetic resonance imaging and gamma scintigraphy was performed at 5, 20, 35 and 50 min after insertion of 3.5 mL of gel. Imaging with a fiberoptic probe was performed at 5 and 20 min after insertion. RESULTS: Initial application of the gel resulted in approximately two thirds of maximum coverage possible, both in linear extent along the vaginal axis and in surface area covered. Over the next 45 min, spreading increased to about three quarters of the maximum possible. Ambulation generally increased linear spreading and the proportions of women with gel at the introitus and os. Effects of parity and body mass index (BMI) were similar on most measures of gel spreading, with nulligravid women tending toward greater spread than parous women and women of high BMI usually showing somewhat greater spread than women of normal weight. Differences between the two gels were not seen when all conditions of application were considered together. CONCLUSION: In vivo imaging of gel distribution demonstrated that ambulation, parity and BMI affect vaginal gel spreading. The three imaging techniques have advantages and disadvantages and provide complementary information for microbicide development.

Gamma scintigraphy for testing bioequivalence: a case study on two cromolyn sodium nasal spray preparations.

The present work was carried out to study the deposition patterns and clearance of technetium-99m (99mTc) DTPA labeled cromolyn sodium (CS) solutions when administered from two different CS nasal products using gamma scintigraphy. Five healthy volunteers received a single dose with complete crossover design involving treatment A (test formulation) and treatment B (reference formulation). The deposition patterns as well as the changes in distribution of the radiolabeled CS solutions due to the mucociliary transport were monitored by gamma scintigraphy. Primary deposition of the aforementioned nasal solutions occurred in the anterior portion of the nose. After migration into the posterior nasal cavity, the solutions were rapidly cleared by ciliary action into the nasopharynx where it was swallowed. The test product of cromolyn sodium was shown to be equivalent to the reference product with regard to nasal deposition and clearance. The results from this study indicate that external gamma scintigraphy can be used to demonstrate the equivalence of nasal sprays that are intended for local therapeutic action where the drug is not systemically absorbed into the blood circulation. Furthermore, a non-invasive imaging method such as rhinoscintigraphy may prove to be a useful technique to be utilized during the regulatory approval process for local-acting nasal products, and may facilitate the early introduction of these products to the market.

Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule.

There are several benefits of oral immunization including the ability to elicit mucosal immune responses that may protect against pathogens that invade through a mucosal surface. Our understanding of human immune biology is hampered by the difficulty in isolating mucosal cells from humans, and the fact that animal models may or may not completely mirror human intestinal immunobiology. In this human pharmacodynamic study, a novel adenovirus vector-based platform expressing influenza hemagglutinin was explored. We used radio-controlled capsules to deliver the vaccine to either the jejunum or the ileum. The resulting immune responses induced by immunization at each of the intestinal sites were investigated. Both intestinal sites were capable of inducing mucosal and systemic immune responses to influenza hemagglutinin, but ileum delivery induced higher numbers of antibody secreting cells of IgG and IgA isotypes, increased mucosal homing B cells, and higher number of vaccine responders. Overall, these data provided substantial insights into human mucosal inductive sites, and aided in the design and selection of indications that could be used with this oral vaccine platform.

Intranasal versus oral administration of lisdexamfetamine dimesylate: a randomized, open-label, two-period, crossover, single-dose, single-centre pharmacokinetic study in healthy adult men.

BACKGROUND AND OBJECTIVE: Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d-amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared. METHODS: In this randomized, two-period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with ≤100 µCi (99m)Tc-diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg ≥7 days apart. Serial blood samples were drawn to measure d-amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Eighteen subjects were enrolled and completed the study. The mean ± SD maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC(last)) of d-amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 ± 4.54 ng/mL and 719.1 ± 157.05 ng · h/mL, respectively; after IN administration, these parameters were 35.9 ± 6.49 ng/mL and 690.5 ± 157.05 ng · h/mL, respectively. PO and IN administration demonstrated similar median time to reach C(max) (t(max)) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t(1/2)) values were also similar for PO (11.6 ± 2.8 hours) and IN (11.3 ± 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects. CONCLUSION: IN administration of lisdexamfetamine dimesylate resulted in d-amphetamine plasma concentrations and systemic exposure to d-amphetamine comparable to those seen with PO administration. Subject variability for d-amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants.