TY - JOUR
T1 - An efficient approach for the rapid assessment of oral rat exposures for new chemical entities in drug discovery
AU - Han, Hyo Kyung
AU - Sadagopan, Nalini
AU - Reichard, Gregory A.
AU - Yapa, Udeni
AU - Zhu, Tong
AU - Hubbel, Andrea
AU - Johnson, Kjell
AU - Brodfuehrer, Joanne
PY - 2006/8
Y1 - 2006/8
N2 - 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 AUG. 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.
AB - 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 AUG. 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.
KW - ADME
KW - Drug design
KW - Drug-like properties
KW - High throughput technologies
KW - Mass spectrometry
KW - Oral absorption
KW - Physicochemical properties
KW - Preclinical pharmacokinetics
KW - Sampling pooling
UR - http://www.scopus.com/inward/record.url?scp=33747193298&partnerID=8YFLogxK
U2 - 10.1002/jps.20642
DO - 10.1002/jps.20642
M3 - Review article
C2 - 16732590
AN - SCOPUS:33747193298
SN - 0022-3549
VL - 95
SP - 1684
EP - 1692
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 8
ER -