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Pharmacokinetic–Pharmacodynamic Modelling of Biomarker Response to Sitagliptin in Healthy Volunteers
Author(s) -
Kim BoHyung,
Kim Sung Eun,
Kang Dongwoo,
Lim Kyoung Soo,
Kim JungRyul,
Jang InJin,
Shin SangGoo,
Yoon Seo Hyun,
Cho JooYoun,
Yu KyungSang
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12068
Subject(s) - sitagliptin , pharmacokinetics , incretin , pharmacodynamics , pharmacology , dipeptidyl peptidase 4 , medicine , sitagliptin phosphate , dipeptidyl peptidase 4 inhibitor , endocrinology , diabetes mellitus , type 2 diabetes
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 E max 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.