title: A Strategy for assessing potential drug-drug interactions of a concomitant agent against a drug absorbed via an intestinal transporter in humans.
abstract: 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.
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.) a-yasuhira@so.taisho.co.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizuno-Yasuhira
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Emi
authors.initials: E
authors.lastname: Gunji
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Saeko
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Teisuke
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Kohnosuke
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Shigeji
authors.initials: S
authors.lastname: Jingu
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Soichi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Samukawa
authors.affiliation: Departments of Drug Safety and Pharmacokinetics Laboratories, Saitama, Japan (A.M.-Y., K.K., S.J., J.Y.) and Molecular Function and Pharmacology Laboratories (E.G., S.U., T.T.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan; Departments of Development Headquarters, (Y.N., Y.S.); and Clinical Research (S.S.), Taisho Pharmaceutical Co. Ltd., Tokyo, Japan (S.S.).
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Yamaguchi
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003198:Computer Simulation; D003412:Cricetulus; D004347:Drug Interactions / Q000502:physiology*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D013012:Sorbitol / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D051269:Sodium-Glucose Transporter 1; C045621:miglitol; D017485:1-Deoxynojirimycin; D013012:Sorbitol; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol