Delay differential equations for the description of Irbesartan pharmacokinetics: A population approach to model absorption complexities leading to dual peaks

Abstract

Irbesartan is a poorly soluble BCS class II compound with weak acidic properties. After oral administration, dual peaks are noted in its concentration (C) – time (t) profile, a phenomenon that may be attributed to enterohepatic recirculation, gastric emptying and/or other absorption complexities related to its pH– and buffer capacity–dependent dissolution behavior. A population pharmacokinetic model, encompassing delay differential equations, was found the most appropriate approach to describe dual peaks in irbesartan's C-t profiles. Parameters estimated were: the absorption rate constant in the central compartment (ka = 0.304 h−1), the constant time delay between the administration and the absorption (T=1.68 h), the apparent volume of distribution of the central (V1/F = 13.8 L) and peripheral (V2/F = 85.8 L) compartment, the apparent clearance from the central compartment (CL/F = 13.5 L/h), and the inter-compartmental clearance (Q/F = 17.7 L/h). Using simulations, it was made evident that changing the time delay results in significant changes of peak plasma concentrations but not of its blood pressure-lowering effect. In conclusion, delay differential equations may be useful to model dual peaks arising from absorption complexities, while changes of the time delay that reflect physiological processes that take place before absorption may have significant implications in proving bioequivalence.