When to consider intra-target microdosing: physiologically based pharmacokinetic modeling approach to quantitatively identify key factors for observing target engagement.

Intra-Target Microdosing (ITM), integral to Phase 0 clinical studies, offers a novel approach in drug development, effectively bridging the gap between preclinical and clinical phases. This methodology is especially relevant in streamlining early drug development stages. Our research utilized a Physiologically Based Pharmacokinetic (PBPK) model and Monte Carlo simulations to examine factors influencing the effectiveness of ITM in achieving target engagement. The study revealed that ITM is capable of engaging targets at levels akin to systemically administered therapeutic doses for specific compounds. However, we also observed a notable decrease in the probability of success when the predicted therapeutic dose exceeds 10 mg. Additionally, our findings identified several critical factors affecting the success of ITM. These encompass both lower dissociation constants, higher systemic clearance and an optimum abundance of receptors in the target organ. Target tissues characterized by relatively low blood flow rates and high drug clearance capacities were deemed more conducive to successful ITM. These insights emphasize the necessity of taking into account each drug's unique pharmacokinetic and pharmacodynamic properties, along with the physiological characteristics of the target tissue, in determining the suitability of ITM.

Pharmacokinetic considerations as to when to use dried blood spot sampling.

In the past few years there has been a large increase in the reporting of the use of dried blood spots (DBS) in drug development. Most of these reports pertain to the technological improvements that have allowed for drug concentration measurements from microliter volumes of sample, issues concerning method development, and exploration of the technique, into other areas such as measurement of macromolecules and metabolite identification. One area that has received less attention and is the subject of this commentary concerns the pharmacokinetic issues that arise from using DBS as opposed to plasma, the mainstay matrix. Measurements of drug concentrations from either plasma or dbs are almost always the sum of bound and unbound drug, but it is the unbound drug in plasma (plasma water) that is the relevant driver of essentially all pharmacokinetic and pharmacodynamic events. Therefore, the critical assumption made is constancy in fraction unbound for plasma, and additionally for blood, constancy of hematocrit and blood cell affinity. Often these assumptions are reasonable and either matrix suffices, but not always. Then the value of one matrix over the other depends on the magnitude of the blood-to-plasma concentration ratio of drug, its clearance and the cause of the deviation from constancy. Additional considerations are the kinetics of distribution within blood and those arising when the objective is assessment or comparison of bioavailability. Most of these issues can be explored and addressed in vitro prior to the main drug development program.