An efficient approach for the rapid assessment of oral rat exposures for new chemical entities in drug discovery

Present study aims to improve efficiency and capacity of in vivo rat pharmacokinetic studies for rapid assessment of systemic exposure (AUC and Cmax) of new chemical entities. Plasma concentration-time profiles in rats from structurally diverse compounds were extracted from the Pfizer database. AUC0-8 was calculated with 7 data points or a reduced subset of 3 data points. AUC values determined with 7 data points were compared to subset AUC values. A ≤ 30% difference in values for 90% of cases was acceptance criteria. In parallel, samples were analyzed individually and pooled at each time point across compounds. For 96% of cases, AUC values estimated using 1, 4, and 8 h were comparable to AUC values obtained from 7 data points suggesting 1, 4, and 8 h sampling should be sufficient to estimate AUC. For Cmax, the difference between 1, 4, and 8 h data-point analysis versus 7 data-point analysis is less than 30% for 72% of cases. Concentrations from individual versus pooled sample analysis were found to be equivalent. A rapid rat PK screening paradigm was created by the combination of 1, 4, and 8 h sampling and pooled sample analysis, which improves throughput and cycle time of in vivo PK studies.