Computer-assembled cross-species/cross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats

Cross-species/cross-modality physiologically based pharmacokinetics for biologics: 89Zr-labelled albumin-binding domain antibody GSK3128349 in humans

“…The default PBPK parameters predicted 13.5 day half-life and 25% renal elimination for albumin in humans, which were shorter and higher relative to the respective experimental observations of 17–19 days 23 , 24 and 3–10%. 25 , 26 Both deviations indicated that the albumin glomerular sieving coefficient 0.0006, as calculated from the 67 kDa molecular weight using an empirical formula described by us before, 14 whilst in agreement with mouse and rat data, 27 was too high for humans. Five-fold adjustment of the glomerular sieving coefficient for free albumin and all albumin-containing complexes to approximately 0.00008, as estimated by Norden et al 28 for humans, increased the terminal half-life to 17.5 days (Supplementary Figure 3) and reduced the fraction of renally eliminated albumin to 6%, both within physiological range.…”

“…In preclinical species, where we explicitly studied the correlation between AlbudAb affinity and plasma half-life, we found that renal elimination played a role only at dissociation constant values above 100 nM. 14 89 Zr-GSK3128349 AlbudAb with subnanomolar affinity for albumin therefore effectively functions as an irreversible label for albumin, and therefore also informs about the tissue distribution kinetics and turnover of this ubiquitous and essential carrier protein for steroids, fatty acids, thyroid hormones, and many small molecule drugs in the blood. 25 …”

“…The initial evaluation of the plasma PK calibrated AlbudAb model predictions against the 89 Zr-GSK3128349 AlbudAb tissue distribution data 15 revealed higher than expected PET signal in the kidneys, while the opposite was found for the brain. Given that 89 Zr is a residualizing radioisotope, unlike 3 H that we used previously in rodents, 14 the model was manually modified, as outlined in the Supplementary section, to evaluate the possible effect of a small fraction of inactive 89 Zr-labeled AlbudAb, or free 89 Zr present in the dose or leaking from the desferrioxamine (DFO) chelator, that may have contributed to the residualized 89 Zr in kidneys and brain. The tissue concentration time profiles were used to run SimBiology global nonlinear least squares fitting task ‘Fit8 Data_org_all’ to estimate the respective parameters, as presented in Table 2 .…”

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Figure 4. Plasma half-life data 14 and best fit for 89 Zr-GSK3128349 AlbudAb in healthy humans. AlbudAb plasma concentration: Blue: measured by mass spectrometry for AlbudAb protein, Red: measured by scintillation and PET for 89 Zr.

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“…Previously we showed in theory and practice that the filtration and diffusion-driven fluxes can be treated as linear functions of the lymph flow rate in such systems, 13 and followed up with an extensive study in mice and rats where the same framework was applied to a number of different biologics to estimate the organ-specific fractional lymph flow rates as the only empirically fitted global parameters. 14 …”