Predicting the Human Hepatic Clearance of Acidic and Zwitterionic Drugs

Prospective predictions of human hepatic clearance for anionic/zwitterionic
compounds, which are oftentimes subjected to transporter-mediated
uptake, are challenging in drug discovery. We evaluated the utility
of preclinical species, rats and cynomolgus monkeys [nonhuman primates
(NHPs)], to predict the human hepatic clearance using a diverse set
of acidic/zwitterionic drugs. Preclinical clearance data were generated
following intravenous dosing in rats/NHPs and compared to the human
clearance data (n = 18/27). Single-species scaling
of NHP clearance with an allometric exponent of 0.50 allowed for good
prediction of human clearance (fold error ∼2.1, bias ∼1.0),
with ∼86% predictions within 3-fold. In comparison, rats underpredicted
the clearance of lipophilic acids, while overprediction was noted
for hydrophilic acids. Finally, an in vitro clearance
assay based on human hepatocytes, which is routinely used in discovery
setting, markedly underpredicted human clearance (bias ∼0.12).
Collectively, this study provides insights into the usefulness of
the preclinical models in enabling pharmacokinetic optimization for
acid/zwitterionic drug candidates.