A modern in vivo pharmacokinetic paradigm: combining snapshot, rapid and full PK approaches to optimize and expedite early drug discovery

Capillary Microsampling of Whole Blood for Mouse PK Studies: an Easy Route to Serial Blood Sampling

“…26 66 [13] Plasma serial sampling 30-50 μl Plasma (10 μl) 10-19 75-87 [3,14] Plasma CMS serial sampling 32 μl Plasma (8 μl) 11 86 [5] Blood CMS serial sampling 8 μl Diluted blood (80 μl)…”

“…If one used a composite sampling strategy (where one takes about 100 μl of blood per sample and up to three samples/mouse), a total of at least 26 mice would have been needed [13]. Most plasma mouse serial sampling methods that have been published rely on taking 30-50 μl of blood and are limited to four to eight total samples/mouse; for these methods, one would still need to use 10-19 mice to get the nine samples/day for two sampling days [3,5,14]. Clearly, a study design based on four mice is better than the alternative higher mouse number designs.…”

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

“…An outline of various in vitro and in vivo DMPK assays used in this study for compound profiling was summarized previously 44 . The pharmacokinetic properties of GNF compounds and calculation of pharmacokinetic parameters was performed as described previously 23 .…”

Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay

“…11 Further handles for installing prodrug functionality exist on the DFSA glycerol side chain. To this end, a series of 8,9-ketals was prepared from intermediate 8 which gave several ketal prodrugs (12) after hydrogenation of the azide. Similarly, cyclic (13) and acyclic carbonates (14) and phosphonates (15) were also prepared by installing the C9 functional group followed by hydrogenation, completing a diverse set of DFSA prodrug compounds (Fig.…”

“…While a snapshot PK screen is a low throughput assay relative to in vitro methods of estimating oral absorption, it is a powerful screening tool that provides real results from an in vivo system for compounds where the correlation between membrane permeability and oral absorption may not be reliable. 12 The snapshot PK screen was performed by dosing mice with the prodrug by oral gavage. Total plasma concentrations of the prodrug and the parent compound were measured at 20 and 60 min time points and the values were compared to the plasma concentration of the parent compound 4 at the same time points using a similar dosing schedule.…”