Phase-0/Microdosing: time for mainstream application in drug development?
A comprehensive review and perspectives article of Phase-0 research, methodologies, and applications. Includes all methodological research and applications in actual drug development of the past two decades.
The burden of the 'false negatives' in drug development
The first comprehensive analysis of the impact of under-powered early-phase studies on the productivity of drug development. Strategic allocation of resources and application of innovative study design features are discussed.
Intra-Target Microdosing (ITM) concept manuscript
This is the ITM concept manuscript describing the theoretical background, range of applications, and modeling support.
First human Intra-Target Microdosing (ITM) study
The study demonstrates the feasibility of ITM in detecting pharmacodynamic and proof-of-mechanism effects in targets of interest by administering a microdose directly to the target. Also demonstrating the utility of control contralateral measurement in modeling extrapolation over the microdose vs. therapeutic-level range.
First ITM proof of concept study in animals
Insulin was administered locally at microdose to generate therapeutic level exposures. Plasma drug and biomarker levels and PET imaging of 18F-FDG uptake into muscle tissue were used as outcomes.
Practical guide to Phase-0 approaches
The article describes the practical aspects of PHase-0 approaches. It emphasizes the importance of initiating planning in advance (1.5.-2 years prior to IND) in order to make full use of the potential of these approaches. It also includes the first economic analysis on the impact of microdosing on the patent life of back-up compounds.
A meta-analysis of 35 microdosing studies
The meta-analysis compares exposures to microdose and therapeutic-level doses. It demonstrates that nearly 80% of drugs administered orally at microdose will extrapolate linearly to therapeutic level exposures. It also demonstrates that if administered IV 100% of the drugs studies extrapolate linearly to therapeutic level exposures.
First randomized withdrawal design in depression
The reason for the design was to have patients stay as little as possible on placebo when symptomatic. Patients on placebo experiencing withdrawal (i.e., resurgence of depressive symptoms) were withdrawn from the study. They were then given standard treatment. The withdrawal event was the primary outcome.
First randomized withdrawal design in psychiatry
The reason for the design was to have patients stay as little as possible on placebo when symptomatic. Patients on placebo experiencing withdrawal (i.e., resurgence of panic symptoms) were withdrawn from the study. They were then given standard treatment. The withdrawal event was the primary outcome.