Preclinical Bridging Studies: Understanding Dried Blood Spot and Plasma Exposure Profiles

Abstract

Statistical analysis of bridging study data is needed to characterize the relationship or concordance between blood (DBS) and plasma. The outcomes also provide guidance on selecting the most appropriate approach to transform DBS data to plasma, or vice versa. However, the biological and statistical evidence must be weighed together when deciding if DBS is suitable for preclinical and/or clinical development.

Sensitive Quantification of Igf-1 and its Synthetic Analogs in Dried Blood Spots

“…Venous and finger-prick DBS concentrations have good agreement with each other with an average bias of 12%. Further characterization of the blood-to-plasma ratio in individuals should allow determination of the variables permitting interconversion between DBS and plasma concentrations [23].…”

“…Multiplex measurement of proteins in DBS shows great potential with Chambers et al identifying 253 proteins in DBS samples and Martin et al using an automated on-spot digest method to identify 120 proteins in a single spot [19,20]. Several reports have examined the analytical challenges of method validation for small molecule analytes in the DBS matrix, including the multiple effects of hematocrit, bloodto-plasma ratio, internal standard addition, spot homogeneity and stability [21][22][23][24]. More work is needed to evaluate the same challenges of the DBS matrix for protein measurement.…”

Dried Blood Spot Analysis for Rat and Dog Studies: Validation, Hematocrit, Toxicokinetics and Incurred Sample Reanalysis

“…This is typically accomplished by generating in vitro blood:plasma (B:P) data or by generating in vivo data [3,[19][20][21]. Understanding the blood-to-plasma (B:P) ratio as well as ruling out any time or concentration dependent differences in the partitioning/association of the drug with the RBCs is important in deciding if one should proceed with using DBS sampling.…”

“…Understanding the blood-to-plasma (B:P) ratio as well as ruling out any time or concentration dependent differences in the partitioning/association of the drug with the RBCs is important in deciding if one should proceed with using DBS sampling. Additionally, once the B:P ratio is known, DBS data can be transformed to plasma equivalents and vice-versa [19].…”

Implementing Dried Blood Spot Sampling for Clinical Pharmacokinetic Determinations: Considerations from the IQ Consortium Microsampling Working Group

“…While DBS can be selected as the sole PK matrix, bridging between liquid samples (plasma, blood, or serum) and DBS at relevant dose/exposure levels (pharmacologic and/or toxicological) in at least one species should be assessed quantitatively for the analyte of interest in order to understand the relationship between the two matrices. Necessary statistical/regression analysis will be helpful in describing this relationship, especially in non-clinical situations where plasma/blood data may have to be compared with DBS data across different studies (35).…”