Microdosing and drug development: past, present and future

Abstract

Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date.

Determination of [ 11 C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging

“…There have been concerns that extrapolation of PK data derived from microdosing could be unreliable and could poorly predict drug disposition of drugs when given at therapeutic doses. However, current evidence suggests otherwise, and in most cases, microdosing is an excellent predictive tool for full-dose human PK, compared with alternative methods (44)(45)(46). Though rapid and noninvasive, PET imaging is limited by its resolution, approximately 1 mm with preclinical scanners, so other techniques will have to be implemented if higher-resolution analyses are required.…”

Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

“…Human microdose studies have been used to verify human PK of drug candidates, particularly when there is uncertainty due to high interspecies variation in preclinical PK properties (39,40). A microdose study can help determine if future development is warranted.…”

Human Micro Dosing Studies (Phase 0): A Novel Approach in Clinical Research

“…Currently there are 35 compounds where micro dose and therapeutic dose data have been compared out of which 27 tested orally showed scalable pharmacokinetics between a micro dose and a therapeutic dose (79 %) and 100 % of those tested intravenously 16 . Present ICH M3 guideline, permits human micro dosing based on a single dose toxicity study in any one animal model, followed by 14 days observation, preferably in the intended route of administration along with an in vitro target receptor data 17 .…”