RT Journal Article
SR Electronic
T1 A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1456
OP 1465
DO 10.1124/dmd.114.058305
VO 42
IS 9
A1 Akiko Mizuno-Yasuhira
A1 Yasuhiro Nakai
A1 Emi Gunji
A1 Saeko Uchida
A1 Teisuke Takahashi
A1 Kohnosuke Kinoshita
A1 Shigeji Jingu
A1 Soichi Sakai
A1 Yoshishige Samukawa
A1 Jun-ichi Yamaguchi
YR 2014
UL http://dmd.aspetjournals.org/content/42/9/1456.abstract
AB A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol Tmax (time for Cmax) value (TAIC/Tmax). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/Tmax in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/Tmax in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter.