Pharmacokinetic-pharmacodynamic modelling of biomarker response to sitagliptin in healthy volunteers.

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.