Rapid in vivo oral screening in rats: Reliability, acceptance criteria, and filtering efficiency

The reliability and acceptance criteria of rapid oral exposure screening were evaluated by pharmacokinetic simulations and by comparing oral exposure of 100 proprietary compounds from 15 therapeutic programs obtained at different times by cassette accelerated rapid rat screen (CARRS) and conventional pharmacokinetic (full-PK) procedures. Once acceptance criteria were established, the filtering efficiency (discard rate) was assessed with a larger data set of 5289 compounds tested by CARRS only. These evaluations indicated that area under the concentration-time curve during the first 6 hours (AUC6h) capture>50% of AUC∞ for most (71%) of the compounds and AUC6h from CARRS is comparable to AUC6h from full-PK in categorizing oral exposure as low, moderate, or high; therefore, the truncated AUC6h derived from pooled plasma samples is suitable for oral exposure screening. The CARRS profiles did not provide reliable half-life estimates; however, compounds with substantial AUC beyond 6 hours can be identified when (C6h/Cmax × 100%) exceeds 80%. Of interest, both the observed data and the simulated data indicated that AUC6h can be estimated using a single time point plasma concentration at 3 hours. The relationship between the maximum biovailability and AUC∞ over a range of clearane values was simulated. A threshold AUC (500 h*ng/mL) at the routine screening dose of 10 mg/kg was established below which a compound can be discarded. Examination of screening results for 5289 compounds evaluated over the last few years in our laboratory indicated that CARRS had a filtering efficiency of 50%, suggesting that this criterion provides a useful decision gate to avoid wasting the drug discovery resources on nonviable candidates.