title: Human pharmacokinetic profiling of the dipeptidyl peptidase-IV inhibitor teneligliptin using physiologically based pharmacokinetic modeling.
abstract: Teneligliptin is a type 2 diabetes drug that has an inhibitory effect on dipeptidyl peptidase-4. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) model to elucidate in detail the pharmacokinetics of teneligliptin. A PBPK model of teneligliptin was developed using the population-based Simcyp simulator incorporating the results of in vitro and in vivo studies. Model validation was conducted by comparison of simulated teneligliptin plasma concentrations with those from clinical trials. Using the PBPK model, predicted drug-drug interactions with concomitant medication were examined. The robustness of the PBPK model was demonstrated by the accurate simulation of clinically measured plasma concentrations of teneligliptin after oral administration in different ethnic groups, in subjects belonging to different age groups and in patients with kidney or liver impairment; none of these factors were incorporated during model development. The fraction absorbed and intestinal availability of teneligliptin predicted by the model were 0.62 and 0.99, respectively. The predicted ratios of areas under the time-concentration curves (AUCs) in patients with moderate and severe renal impairment who were concomitantly administered ketoconazole, a potent inhibitor of P450 3A4, were, respectively, 2.1- and 2.2-fold those in healthy adults who were given teneligliptin alone. A robust PBPK model reflecting the pharmacokinetic properties of teneligliptin was constructed. The final optimized PBPK model enabled us to elucidate in detail the factors affecting the pharmacokinetics of teneligliptin and to predict changes in exposure in drug-drug interactions or in specific populations.
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan; Mitsubishi Tanabe Pharma Co, Kisarazu, Chiba, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nakamaru
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000378:metabolism; D015203:Reproducibility of Results; D053778:Thiazolidines / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D065692:Cytochrome P-450 CYP3A Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011720:Pyrazoles; D053778:Thiazolidines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole
keywords: DPP-4 inhibitor; PBPK modeling; drug-drug interaction; teneligliptin