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 (V_d) was well predicted using allometric scaling of animal pharmacokinetic data; the most reliable results were achieved using simple allometric scaling of unbound V_d values. These results provide a quantitative framework to guide appropriate method selection for human PK prediction with covalent drugs.