Predicting the Intravenous Pharmacokinetics of Covalent Drugs in Animals and Humans

30 covalent drugs were used to assess clearance (CL)
prediction
reliability in animals and humans. In animals, marked CL underprediction
was observed using cryopreserved hepatocytes or liver microsomes (LMs)
supplemented for cytochrome P450 activity. Improved quantitative performance
was observed by combining metabolic stability data from LMs and liver
S9 fractions, the latter supplemented with reduced glutathione for
glutathione transferase activity. While human LMs provided reliable
human CL predictions, prediction statistics were improved further
by incorporating S9 stability data. CL predictions with allometric
scaling were less robust compared to in vitro drug metabolism methods;
the best results were obtained using the fu-corrected intercept model.
Human volume of distribution (Vd) was well predicted using
allometric scaling of animal pharmacokinetic data; the most reliable
results were achieved using simple allometric scaling of unbound Vd values. These results provide a quantitative framework to
guide appropriate method selection for human PK prediction with covalent
drugs.