Use of Preclinical Dog Studies and Absorption Modeling to Facilitate Late Stage Formulation Bridging for a BCS II Drug Candidate
Journal Title: AAPS PharmSciTech - Year 2014, Vol 15, Issue 1
Abstract
Formulation changes are common during drug development either due to clinical or manufacturing considerations. These changes especially at later stages of drug development oftentimes raise questions on the potential impact of a new formulation on bioavailability. In this work, the preclinical assessment of formulation bridging risk for a Biopharmaceutics Classification System II development compound is presented. Early clinical studies were conducted using a liquid-filled capsule (LFC). To assess the feasibility of a conventional solid dosage form, an initial analysis was conducted using absorption modeling which indicated conventional formulation of micronized active pharmaceutical ingredient (API) could be a viable option. Subsequently, test formulations were prepared and tested in vivo in dogs. The solid formulations were able to match exposures of the LFC capsule in the dog model; in addition, a sensitivity to API PSD was observed in line with the modeling predictions. When tested in the clinic, the conventional solid formulation resulted in exposures of approximately 25% lower compared to the LFC on an equivalent dose basis; however, bridging with a small dose adjustment would be feasible. The outcome of the clinical study was better predicted by the modeling approach while the dog model appeared to somewhat overestimate absorption. Through the use of preclinical tools and modeling and simulation, a risk assessment around formulation bridging can be conducted and inform formulation decisions or subsequent clinical study designs.
Authors and Affiliations
Filippos Kesisoglou
Keywords
Related Articles
- EP ID EP682327
- DOI 10.1208/s12249-013-0030-6
- Views 101
- Downloads 0
Development of Modified-Release Tablets of Zolpidem Tartrate by Biphasic Quick/Slow Delivery System
Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration...
Transcutaneous Peptide Immunotherapy of Japanese Cedar Pollinosis Using Solid-in-Oil Nanodispersion Technology
The online version of this article (doi:10.1208/s12249-015-0333-x) contains supplementary material, which is available to authorized users.
A Self-microemulsifying Drug Delivery System (SMEDDS) for a Novel Medicative Compound Against Depression: a Preparation and Bioavailability Study in Rats
AJS is the code name of an untitled novel medicative compound synthesized by the Tasly Holding Group Company (Tianjin, China) based on the structure of cinnamamide, which is one of the Biopharmaceutics Classification Sys...
Development of Novel Docetaxel Phospholipid Nanoparticles for Intravenous Administration: Quality by Design Approach
The objective of this study was to develop novel docetaxel phospholipid nanoparticles (NDPNs) for intravenous administration. Modified solvent diffusion-evaporation method was adopted in the NDPN preparation. Central com...
Lipid Effects on Expulsion Rate of Amphotericin B from Solid Lipid Nanoparticles
We aimed to investigate the effects that natural lipids, theobroma oil (TO) and beeswax (BW), might have on the physical properties of formulated nanoparticles and also the degree of expulsion of encapsulated amphoterici...