title: An efficient approach for the rapid assessment of oral rat exposures for new chemical entities in drug discovery.
abstract: 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.
authors.affiliation: College of Pharmacy, Cho-Sun University, Seosuk-dong, Gwangju, Korea.
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
authors.forename: Nalini
authors.initials: N
authors.lastname: Sadagopan
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reichard
authors.forename: Udeni
authors.initials: U
authors.lastname: Yapa
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Andrea
authors.initials: A
authors.lastname: Hubbel
authors.forename: Kjell
authors.initials: K
authors.lastname: Johnson
authors.forename: Joanne
authors.initials: J
authors.lastname: Brodfuehrer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000097:blood*; D051381:Rats; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations