PII-107

K. Yoshida,1 C. K. Yeung,2 M. Kusama,3 H. Zhang,1 I. Ragueneau-Majlessi,2 S. Argon,2 P. Zhao,1 L. Zhang,1 I. Zineh,1 Y. Sugiyama,4 S. Huang1; 1US Food and Drug Administration, Silver Spring, MD, 2University of Washington, Seattle, WA, 3The University of Tokyo, Tokyo, Japan, 4The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan

BACKGROUND: It has been shown that renal impairment (RI) can affect the pharmacokinetics of nonrenally eliminated drugs. Current regulatory guidances by FDA and EMA recommend considering “reduced” RI studies with only one group of RI patients for these drugs. However, no systematic evaluation has been performed to determine which group of RI patients provides the “worst case scenario” in regards to changes in systemic exposure.
METHODS: Changes in AUC or clearance values of 90 nonrenally eliminated drugs in RI or HI patients were collected systematically using the University of Washington Metabolism and Transport DatabaseTM and Drugs@FDA. AUC ratios (AUCR) were calculated for each study (AUC with RI /AUC without RI or AUC with HI /AUC without HI), and AUCR in different groups of patients were compared.
RESULTS: See Figure.
CONCLUSION: The results showed consistent findings with previous observations that RI can increase systemic exposure even for nonrenally eliminated drugs. In addition, our analysis suggests that the “severe” RI group may be the most appropriate group to provide the “worst case scenario” of overexposure of nonrenally eliminated drugs in a renal impairment situation. The results also suggest that the observed AUC increase in RI patients cannot be explained solely by concurrent modifications in hepatic function.