An efficient approach for the rapid assessment of oral rat exposures for new chemical entities in drug discovery
✍ Scribed by Hyo-Kyung Han; Nalini Sadagopan; Gregory A. Reichard; Udeni Yapa; Tong Zhu; Andrea Hubbel; Kjell Johnson; Joanne Brodfuehrer
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 216 KB
- Volume
- 95
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
Present study aims to improve efficiency and capacity of in vivo rat pharmacokinetic studies for rapid assessment of systemic exposure (AUC and C(max)) of new chemical entities. Plasma concentration-time profiles in rats from structurally diverse compounds were extracted from the Pfizer database. AUC(0-8) 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 < or = 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 C(max), 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.