Walter J. Doll

An in vitro-in vivo investigation of oral bioadhesive controlled release furosemide formulations☆

Abstract The in vitro controlled release and bioadhesive properties of furosemide formulations were evaluated with standard dissolution tests and with a specially developed model using rabbit intestine. The results showed that the controlled release properties were not affected by the application of the bioadhesive polymer but that the bioadhesive properties were substantially different. In order to assess the gastrointestinal transit time in vivo, a γ-scintigraphy study was performed in six volunteers testing the same controlled release formulation with and without bioadhesive polymer. Plasma levels of furosemide, evaluation of urinary flux and measures of urinary excretion of furosemide in the six volunteers allowed correlations to be made between gastrointestinal transit and furosemide absorption.

Bioequivalence Study of Stressed and Nonstressed Hard Gelatin Capsules Using Amoxicillin as a Drug Marker and Gamma Scintigraphy to Confirm Time and GI Location of In Vivo Capsule Rupture

AbstractPurpose: Evaluate if crosslinked hard gelatin capsules (HGCs) havingdifferent in vitro dissolution profiles changed in vivo release times oraltered bioavailability of a drug marker; assess if a two-tier dissolutiontest (with and without enzyme) predicted in vivo performance. Methods. Two classifications of stressed HGCs were artificiallyproduced by exposure to formaldehyde (HCHO). HGCs were categorizedas, a) pass/pass (p/p) which met in vitro dissolution criterion (75%drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p)which failed dissolution criterion in the absence of enzymes and passedin the presence of enzymes, and c) severely crosslinked fail/fail (f/f)which failed in vitro standards with or without enzymes. A six-way,single dose bioequivalence study (n = 10) administered the three HGCsunder the fasted and fed condition. In vivo capsule rupture and GItransit were monitored via gamma scintigraphy, and blood sampleswere collected through six hours. Results. Each crosslinked HGC was bioequivalent to the control p/pcapsule when using AUC(0−∞) and Cmax for comparison. Meanin vivo disintegration of the p/p capsule was 7 ± 5 min for the fastedcondition and 11 ± 7 min for the fed condition. In vivo rupture forthe f/p capsule was 22 ± 12 min and 23 ± 11 min for the fasted andfed studies, respectively, while the f/f HGC ruptured at 31 ± 15 minand 71 ± 19 min under the fasted and fed condition, respectively.Onset of amoxicillin absorption was dependent on in vivo HGC ruptureand subsequent entry of the released radioactive marker into the smallintestine. Consequently, fasted Tmax values were significantly laterfor the f/p HGC (1.62 ± 0.53 hr) and f/f HGC (1.85 ± 0.58 hr) ascompared to the p/p HGC (1.17 ± 0.30 hr). Fed Tmax values werestatistically different only for the f/f capsule (2.55 ± 0.44 hr) whereTmax values for the p/p and f/p HGCs under the fed condition were1.50 ± 0.47 hr and 1.60 ± 0.46 hr, respectively. Conclusions. A two-tier dissolution procedure that retested across-linked hard gelatin capsule with addition of gastric or intestinal enzymesprovided an adequate in vitro indicator of the formulationsin vivo performance. The observed delays in the onset of amoxicillin absorptionand Tmax for the severely crosslinked f/f HGC was attributed todelayed in vivo capsule rupture, however, this delay did not adverselychange AUC(0−∞) nor Cmax.

Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate

AbstractBackground 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 99mTc-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 (Cmax) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) 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 Cmax (tmax) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t1/2) 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.

Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended‐release formulation of an HIV‐1 attachment inhibitor phosphate ester prodrug

BMS-663068 is a phosphonooxymethyl ester prodrug under development for the treatment of HIV/AIDS. The prodrug is designed to overcome the solubility-limited bioavailability of the active moiety, BMS-626529. BMS-663068 is not absorbed from the gastrointestinal (GI) tract and requires enzymatic conversion by alkaline phosphatase to BMS-626529 immediately before absorption. In the light of the known short in vivo half-life of BMS-626529, compartmental absorption modeling was used to predict the potential feasibility of extended-release (ER) delivery to achieve target Cmax :Cmin ratios. To further refine the model with respect to colonic absorption, the regional absorption of BMS-626529 following delivery of BMS-663068 to upper and lower GI sites was characterized through a site of absorption study in human subjects. A refined model was subsequently applied to guide the development of ER tablet formulations. Comparisons of results from the refined model to the in vivo human pharmacokinetic data for three selected ER formulations demonstrate the utility of the model in predicting feasibility of ER delivery and in directing formulation development.

In Vivo Evaluation of the Absorption and Gastrointestinal Transit of Avitriptan in Fed and Fasted Subjects Using Gamma Scintigraphy

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive152samarium chloride hexahydrate which was neutron-activated to gamma-emitting153samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration–time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration–time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.

Biodegradable indium-111 labeled microspheres for in vivo evaluation of distribution and elimination

Short-lived gamma emitting radioisotopes can be incorporated into polylactide/glycolide polymeric microspheres with various specific activities for possible use in understanding the in-vivo deposition, distribution and clearance of microparticulate drug carrier systems. The incorporated radiolabel is stable with negligible leaching out of the microspheres. These microspheres are suitable for studying the oral uptake of particles, lung distribution after inhalation delivery and evaluation of in-vivo fate following parenteral administration in systemic circulation or in specific tissue compartments.

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 (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.

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.

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. Copyright