Deriving Clearance and Bioavailability from Oral Clinical PK Studies with Information on Fraction Absorbed, Including Radiolabeled Mass-Balance Studies.

Human radiolabeled mass-balance studies are central to characterizing drug absorption, distribution, metabolism, and excretion (ADME), but oral-only designs do not directly provide absolute oral bioavailability (F) or systemic clearance (CL). In this study, we evaluated whether F and CL can be estimated from oral pharmacokinetic (PK) data when the fraction absorbed (Fa) and renal clearance (CLr) are known. We derived equations linking oral apparent clearance (CL/F), hepatic extraction, and bioavailability, and tested two assumptions for intestinal first-pass extraction (Fg=1 and Fg=Fh). The approach was validated using 120 approved oral small-molecule drugs with published oral human ADME and intravenous pharmacokinetic data. Predicted CL values were within 2-fold of observed values for 97-99% of drugs and predicted F values were within 2-fold for 98-99%. 64-68% of CL estimates and 74-77% of F estimates were within 80-125% of the observed values. These findings show that oral PK combined with Fa and CLr can provide useful early estimates of F and CL without an intravenous study, supporting drug development and clinical pharmacology study planning.