Estimation of absolute oral bioavailability without performing an intravenous clinical study

Abstract

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R_u) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (f_e) was calculated for healthy subjects by dividing the R_u value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (R_ren) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as f_e/R_ren and compared with the observed BA (BA_obs). The predicted BA values for 9 drugs fell within ±20% of their BA_obs. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.

Keywords: Creatinine; GFR; Oral bioavailability; Renal dysfunction; Renal excretion.