2007 - KÝbenhavn - Denmark

PAGE 2007: Applications- Endocrine
Silke Retlich

Determination of the absolute bioavailability of BI 1356, a substance with non-linear pharmacokinetics, using a population pharmacokinetic modelling approach

Dittberner, S. (1), V. Duval (2), A. Staab (2), I. Troconiz (3), U. Graefe-Mody (2), U. Jaehde (1)

(1) Dept. Clinical Pharmacy, Institute of Pharmacy, Rheinische Friedrich-Wilhelms-Universitšt Bonn, Bonn, Germany; (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d.R., Germany; (3) School of Pharmacy, University of Navarra, Pamplona, Spain

Objectives & Background: BI 1356 is a new dipeptidyl-peptidase IV (DPP IV) inhibitor under clinical development for type 2 diabetes mellitus. BI 1356 exhibits non-linear pharmacokinetics most likely caused by a concentration-dependent protein binding to its target protein DPP IV. The non-linearity makes it difficult to determine the absolute bioavailability using non-compartmental analysis. Therefore the objective of this analysis was to develop a model with a physiologically plausible explanation for the non-linear pharmacokinetics and to use this model to determine the absolute bioavailability. In addition, urine data were used to confirm the model structure. The urinary elimination is assumed to be dependent only on the unbound concentration and therefore provides additional information about the binding. The model is based on healthy volunteer pharmacokinetic data from an intravenous single rising dose study including a crossover arm with oral administration for the estimation of the absolute bioavailability.

Methods: Single dose plasma concentration-time profiles of 28 healthy volunteers (0.5, 2.5 or 10 mg BI 1356 intravenously, or 5 mg intravenously plus 10 mg BI 1356 orally) consisting of 862 BI 1356 plasma and 304 urine concentrations were included in the population PK analysis. The modelling was performed using the FOCE INTERACTION estimation method implemented in NONMEM V.

Results & Discussion: Plasma concentration-time profiles of BI 1356 in healthy volunteers were best described by a three-compartment model with concentration-dependent protein binding in the central and in one peripheral compartment. The absorption of BI 1356 was modelled using a first-order process. Inter-individual variability was estimated on the absorption parameters (Ka, Lag time and F). Using this model it was possible to determine the absolute bioavailability of BI 1356 despite its non-linear pharmacokinetics. The absolute bioavailability was estimated to be around 30 %. It is most likely that the concentration-dependent protein binding in the central and the peripheral compartment represents binding of BI 1356 to DPP IV available in both plasma and tissue (e.g. kidney, liver, lung). The urine data were best modelled assuming a linear urinary elimination of the unbound concentration of BI 1356. The parameter estimates were nearly identical to those obtained using only the plasma data. The urine data from the 0.5 mg intravenous dose group was slightly overpredicted, however no alternative model tested described the data better. These results confirm the model structure and suggest that the urine data could be explained without an additional non-linear process.

Conclusions: A population pharmacokinetic model including physiological knowledge showed that the non-linear plasma and urine pharmacokinetics of BI 1356, a new DPP IV inhibitor, could be explained by concentration dependent protein binding, most likely to its target protein. Using this model it was possible to determine the absolute bioavailability of BI 1356 despite its non-linear pharmacokinetics. The absolute bioavailability was estimated to be around 30 %.




Reference: PAGE 16 (2007) Abstr 1110 [www.page-meeting.org/?abstract=1110]
Poster: Applications- Endocrine
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