BI 1356 (proposed trade name ONDERO) pharmacokinetics and DPP-4 inhibition: Development of a target mediated PKPD model in type 2 diabetic patients
S. Dittberner (1), V. Duval (2), A. Staab (2), U. Graefe-Mody (2), U. Jaehde (1)
(1) Dept. Clinical Pharmacy, Institute of Pharmacy, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany; (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d.R., Germany
Objectives: BI 1356 is a novel, highly selective and long acting DPP-4 inhibitor under development for type 2 diabetes mellitus (T2DM). BI 1356 exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of the analysis was to characterize the relationship between PK and DPP-4 activity (normalized to pre-dose DPP-4 activity) in T2DM patients by means of a physiologically plausible population pharmacokinetic/pharmacodynamic (PKPD) model.
Methods: PK and DPP-4 inhibition data from 2 placebo-controlled, multiple oral dose, parallel group studies that included 124 T2DM patients (96 on BI 1356 treatment) were used for the analysis. In study 1, doses of 1, 2.5, 5 and 10 mg of BI 1356 were administered once daily as a powder in the bottle formulation for 12 days. In study 2, doses of 2.5, 5 and 10 mg of BI 1356 tablets were taken once daily for 28 days. The modelling was performed using the FOCE INTERACTION estimation method implemented in NONMEM V.
Results: The non-linear PK in patients was best described by a two compartment model that took concentration-dependent binding to DPP-4 in the central and peripheral compartment into account. The amount of binding sites was allowed to be different in the central and peripheral compartment, whereas the affinity was assumed to be identical. Inter-patient variability was established for the parameters F1, KA and for the concentration of central binding sites and intra-patient variability was accounted for on F1.
The plasma DPP-4 activity was linearly correlated with the estimated DPP-4 occupancy in plasma. The concentration of central binding sites estimated by the model correlated well with the pre-dose DPP-4 activity raw data, supporting the hypothesis that these binding sites reflected the actual plasma DPP-4 concentration.
Conclusions: A PKPD model for a novel DPP-4 inhibitor was developed that integrated both non-linear PK and DPP-4 inhibition data from T2DM patients. The model was based on the assumption of target protein (DPP-4) binding in both plasma and peripheral tissue. The occupancy of DPP-4 in plasma was successfully used to relate PK to DPP-4 inhibition in plasma. Thus based on physiological knowledge, this model allows informative simulations and will serve as a basis for covariate analyses.