Pharmacokinetic Considerations as to When to Use Dried Blood Spot Sampling

Abstract

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.

Dried Blood Spot Analysis Suitable for Therapeutic Drug Monitoring of Voriconazole, Fluconazole, and Posaconazole

“…The concentrations of all triazoles in DBS samples were in good agreement with those in plasma. Previous studies on DBS analysis showed that the hematocrit value and the blood spot volume may influence the analysis results for DBS samples (31)(32)(33)39). For analysis of the triazoles, the hematocrit value and blood spot volume had only a minor influence.…”

“…Concentrations of posaconazole in plasma were slightly higher than those in DBSs. This difference might be caused by a difference in protein binding, which is Ͼ98% for posaconazole (18), or the different distributions of the drug in whole blood and plasma, since the same difference was also observed between concentrations in VDBS and plasma samples (39). Although labeled isotopes are preferred as internal standards when mass spectrometry is used, with the use of cyanoimipramine as an internal standard, no ion suppression was observed during analysis of six lots of pooled human serum and the simultaneous direct infusion of a stock solution containing fluconazole, voriconazole, or posaconazole and cyanoimipramine (34).…”

“…Differences in protein binding and in the distribution of a drug between whole blood and plasma can lead to different concentrations of the drug in whole blood and plasma. Furthermore, the concentration of a drug in capillary blood obtained by finger pricking is a mixture of venous and arterial blood and mimics arterial rather than venous sampling (39). Clinical validation with patients' DBS samples is therefore required to make sure that DBS samples can be used as a substitute for plasma samples.…”

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

“…In previous studies on DBS analysis of other drugs, several technical factors were pointed out that have to be considered when interpreting DBS analysis, such as the effect of Hct and blood spot volume (12,13,18,30). For the analysis of linezolid in DBS samples, the effect of Hct seemed to be of minor concern.…”

Development of an UPLC–MS/MS method for the determination of antibiotic ertapenem on dried blood spots

“…DBS specimens are commonly used for neonatal screening of metabolic diseases, cystic fibrosis and hypothyroidism in micro-blood samples. Some studies recently evaluated the use of DBS for therapeutic drug monitoring (TDM) and toxicology in adults [9,10]. Some studies, also from our group, applied the DBS technique to evaluate drug concentrations in newborns, infants and children [11][12][13][14][15].…”