The expanding utility of microdosing

The concept of microdosing has been around for more than a decade. It consists of the subpharmacologic administration of an investigational drug (1% of the pharmacologic dose or 100 µg, whichever is lower) to human subjects to attain pre–phase 1 pharmacokinetics (PK) in humans. The major concern with microdosing has been the potential for nonlinear PK between doses, but methods are emerging to evaluate the potential for nonlinear PK prior to conducting a study. Currently, approximately 80% of drugs tested by the oral route and 100% by the intravenous route have exhibited scalable PK between a microdose and a therapeutic dose (within a factor of 2). Over the past few years microdosing has found utility in pediatrics, protein‐based therapeutics, and a new application known as intra‐arterial microdosing that focuses more on localized pharmacodynamics than PK. Compared with other PK predictive methods, such as physiologically based pharmacokinetic modeling, allometry, and in vitro–in vivo extrapolation, microdosing appears to provide a significantly better understanding of PK prior to phase 1, albeit within what is currently a limited database.