title: Pharmacokinetic-pharmacodynamic modelling of biomarker response to sitagliptin in healthy volunteers.
abstract: Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one-sequence, three-period, repeated-dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first-in-man study for the newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP-4 activity and active glucagon-like peptide-1 (GLP-1) concentrations. In study 2, only data from the 'placebo group' were used, and blood samples were collected to measure DPP-4 activity, active GLP-1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non-linear mixed effects modelling approach. Sitagliptin pharmacokinetics was modelled using a two-compartment model with first-order absorption. Changes in DPP-4 inhibition were linked to the PK model using a sigmoid Emax model, whereas the active GLP-1 changes were explained using an indirect response model; this model incorporated the glucose and DPP-4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP-4 inhibition and active GLP-1 concentration in healthy volunteers.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Kang
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lim
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D011719:Pyrazines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate