Use of Dried Blood Spots in Drug Development: Pharmacokinetic Considerations

Abstract

Abstract. Dried blood spots are increasingly being used in drug development. This commentary considers the pharmacokinetic issues that arise and compares these with those attached to plasma, the mainstay matrix. A common implicit use of these matrices is as a surrogate for plasma water, and to this extent, the critical assumption made is constancy in fraction unbound for plasma and, additionally for blood, constancy of hematocrit and blood cell affinity of compound. Often, these assumptions are reasonable and either matrix suffices, but not always. Then the value of one over the other matrix 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.

Potassium-based algorithm allows correction for the hematocrit bias in quantitative analysis of caffeine and its major metabolite in dried blood spots

“…The same algorithm, initially designed for caffeine, was applied to a separate compound, paraxanthine, yielding similar results. Caffeine and paraxanthine are weakly basic compounds that show low binding to plasma or red blood cell proteins [5]. To further support the broader applicability of the presented approach, its usefulness should be evaluated for more analytes, displaying varying physicochemical properties and binding characteristics, The latter should include, amongst others, neutral, acidic and basic compounds, hydrophilic and hydrophobic 9 substances and analytes with different plasma protein binding and blood cell association profiles.…”

“…The physiological facet of the Hct issue, on the other hand, relates to the influence of the Hct on the blood-to-plasma concentration ratio of an analyte. The latter is of key importance when DBS results are to be compared with established plasma-or serum-based reference intervals or therapeutic ranges [5].…”

Why Dried Blood Spots Are an Ideal Tool for CYP1A2 Phenotyping

“…As caffeine and most probably also paraxanthine (given their structural similarity) exhibit low binding to plasma proteins and freely enter blood cells without binding to cellular proteins, plasma and blood concentrations should be very similar. Taking into account the fraction of solid constituents in blood, the blood concentration could be expected to lie approximately 15% lower than the plasma concentration [9,30]. The observed differences (15.2 and 16.6% for caffeine and paraxanthine, respectively) are in line with this expectation.…”

“…First of all, being a capillary sampling technique, the correlation between venous and capillary concentrations is one of the key points that needs to be evaluated when setting up DBS-based methods [7,8]. Furthermore, adequate interpretation of DBS results requires comparison with plasma or serum concentrations, as clinical reference intervals are commonly based on the latter [9]. Finally, potential bias introduced by the spotting technique itself must be excluded, for example by comparing concentrations measured in venous whole blood samples with concentrations in venous DBS.…”

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…In this light, thorough interpretation of DBS results often requires comparison with DBS and plasma/serum results, as reference intervals or cut-off values are commonly based on the latter [34].…”