An Integrated Strategy for Implementation of Dried Blood Spots in Clinical Development Programs
Journal Title: The AAPS Journal - Year 2016, Vol 18, Issue 2
Abstract
Dried blood spot (DBS) sample collection has gained increased interest across the pharmaceutical industry as a potential alternative to plasma for pharmacokinetic (PK) evaluations. However, regulatory guidelines and examples of late-stage clinical trial applications in the literature are lacking. This paper communicates Merck’s strategy for the implementation of DBS exemplified by experience on a late-stage program (MK-8931). In this program, DBS was proposed as the sole matrix for phase 3 studies to decrease logistical burden in an aging target patient population (Alzheimer’s disease). In vitro and bioanalytical tests demonstrated initial method feasibility and suitability for further evaluations in the clinic. An in vivo dataset was developed initially in healthy subjects (phase 1 study) and then in patients (phase 2/3 study) to establish a quantitative relationship between the blood and plasma concentrations (bridging dataset) using descriptive and population PK analyses. This allowed for PK conclusions to be seamlessly drawn across the clinical program without impact from the choice of matrix. This integrated information package (in vitro, bioanalytical and clinical) was presented to major regulatory agencies (FDA and EMA) for regulatory input. Based on this package, regulatory concurrence was gained on accepting DBS as the sole matrix in late-stage clinical trials.
Authors and Affiliations
Prajakti A. Kothare, Kevin P. Bateman, Marissa Dockendorf, Julie Stone, Yang Xu, Eric Woolf, Lisa A. Shipley
Keywords
Related Articles
- EP ID EP680861
- DOI 10.1208/s12248-015-9860-3
- Views 71
- Downloads 0
A thermogravimetric analysis of non-polymeric pharmaceutical plasticizers: Kinetic analysis, method validation, and thermal stability evaluation
Four non-polymeric plasticizers, propylene glycol, diethyl phthalate, triacetin, and glycerin have been subjected to rising temperature thermogravimetry for kinetic analysis and vaporization-based thermal stability evalu...
CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48
The online version of this article (doi:10.1208/s12248-015-9788-7) contains supplementary material, which is available to authorized users.
Selected physical and chemical properties of commercial Hypericum perforatum extracts relevant for formulated product quality and performance
Objective. The complex composition-activity relationship of botanicals such as St John's Wort (SJW) presents a major challenge to product development, manufacture, and establishment of appropriate quality and performance...
Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs
Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are dis...
Endocannabinoid mechanisms of pain modulation
Cannabinoids are antinociceptive in animal models of acute, tissue injury-, and nerve injury-induced nociception. This review examines the biology of endogenous cannabinoids (endocannabinoids) and behavioral, neurophysio...