Optimization of LY545694 Tosylate Controlled Release Tablets Through Pharmacoscintigraphy

Lobo, Evelyn D.; Argentine, Mark D.; Sperry, David C.; Connor, Alyson; McDermott, John; Stevens, Lloyd; Almaya, Ahmad

doi:10.1007/s11095-012-0798-1

Cited by 11 publications

(4 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The scintigraphic data were analyzed using MicasXplus processing software as previously described. 16 To avoid bias, these analyses were performed blinded to the amount of water volume with dosing.…”

Section: Assessmentsmentioning

confidence: 99%

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study

Bækdal

Donsmark

Hartoft‐Nielsen

et al. 2021

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the semaglutide concentrationtime curve from 0 to 24 hours (AUC 0-24h,semaglutide ) and maximum semaglutide concentration (C max,semaglutide ) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (t max,semaglutide ) was 1.5 hours independent of water volume with dosing. Higher AUC 0-24h,semaglutide and C max,semaglutide and longer t max,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP-1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.

show abstract

Section: Assessmentsmentioning

confidence: 99%

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study

Bækdal

Donsmark

Hartoft‐Nielsen

et al. 2021

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

show abstract

“…A new CR formulation prototype with variable drug release rates was developed by adjusting the polymer composition of the tablet, the dose was lowered and the formulation radiolabeled to support scintigraphic imaging to visualize and quantify in vivo tablet performance. A crossover study was conducted in healthy volunteers and the formulation was assessed using emerging clinical data; interim decisions on its performance were based on pharmacokinetic and scintigraphic imaging data ( Lobo et al, 2012 ). Two more formulation prototypes were assessed using the 14-day “make-test” cycle.…”

Section: Integrating Adaptive Pharmaceutical and Clinical Strategies mentioning

confidence: 99%

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting 2018: Brexit and Other Challenges in Early Phase Drug Development

Reijntjes¹,

Albayaty

Bush

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on the changing face of early phase drug development and opened with a keynote speech concerning the revolution in pharmaceutical medicine over the last 30 years and the impact this has had on the way patients are treated. Examples were presented of how translational pharmaceutics is being used to tackle the high drug candidate failure rate and is improving productivity when moving drug candidates from the laboratory through to clinical proof of concept. The European Medicines Agency revised 2007 Risk Mitigation guideline on first in human (FIH) clinical trials was discussed. The focus of the revised guideline, which came into force in February 2018, is on risk mitigation and promotion of safety and will assist drug sponsors with the design and performance of early clinical studies. The use of integrated adaptive protocol designs in early clinical development was discussed in relation to the challenges involved when running early phase clinical trials in patients. The Health Regulatory Authority presented its strategies to ensure that following Brexit, the United Kingdom remains an attractive place to conduct Phase I clinical trials. The Medicines and Healthcare products Regulatory Agency confirmed that in the event of a “no deal” Brexit, it is well placed to implement and influence many provisions of the new EU CTR. The meeting provided an opportunity to discuss the changing regulatory environment and the opportunities and challenges facing the United Kingdom following Brexit with invited speakers from a range of disciplines including drug development, clinical trials and research organizations, government science policy and regulatory agencies.

show abstract

“…In the investigation reported by Lobo and colleagues, three prototype hydrophilic matrix formulations (containing LY545694 tosylate) with drug release ranging from 3.5 to 8 h were compared with a reference controlled release formulation [ 44 ]. In vitro, the formulation with a 6 h release profi le (prototype 1) was observed to release more quickly than the reference controlled release formulation.…”

Section: Scintigraphic Imaging and Pharmacokinetic Case Studiesmentioning

confidence: 99%

“…9.5.2 , radiolabelling of MR dosage forms for scintigraphic imaging allows direct in vivo visualisation of dosage form performance. A recent publication has described how the combined use of a formulation design space coupled with PK and scintigraphic end points enabled the effective optimisation of a second-generation MR formulation for LY545694 Tosylate, a prodrug for compound 645838 [ 44 ]. To overcome dose-limiting adverse events from immediate release dosage forms, an initial 35mg MR formulation (Methocel ® K4M Premium CR, 80 % targeted release over 8-10 h) had been developed.…”

Section: Product Optimisation Using a Two Dimensional Design Spacementioning

confidence: 99%

Approaches to Rapid In Vivo Optimization of Hydrophilic Matrix Tablets

McDermott

Scholes

Lin

et al. 2014

Hydrophilic Matrix Tablets for Oral Controlled Release

Self Cite

View full text Add to dashboard Cite

An effective hydrophilic matrix tablet must deliver a stable stream of active compound at an optimal rate to the gastrointestinal (GI) tract in order to achieve a benefi cial therapeutic effect. It must do this whilst moving through the GI tract, passing through a range of different environments, and experiencing environmental changes in pH, fl uid volume, fl uid composition, and physical forces, whilst also accounting for regional changes in drug absorption.In addition to this variable environment, the physico-chemical and biopharmaceutical properties of new drugs (or NCE, "new chemical entities") emerging from the industry R&D pipeline increasingly possess suboptimal solubility [ 1 ] and and/ or permeability characteristics which have an infl uence on the drug delivery. When tasked with developing a hydrophilic matrix tablet formulation, the development team must therefore rationalise these many parameters in order to meet the target product profi le (TPP).Traditional formulation development studies involve expensive and timeconsuming screening of multiple prototypes in preclinical species, in order to identify a limited number of "lead" systems to then take forward into human clinical pharmacokinetic (PK) studies (Fig. 9.1 ). This process can cost over $1.5M and take 12-15 months [ 2 ].

show abstract

Optimization of LY545694 Tosylate Controlled Release Tablets Through Pharmacoscintigraphy

Cited by 11 publications

References 18 publications

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study

Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting 2018: Brexit and Other Challenges in Early Phase Drug Development

Approaches to Rapid In Vivo Optimization of Hydrophilic Matrix Tablets

Contact Info

Product

Resources

About