Category: Clinical Pharmacology
Purpose: Irbesartan presents highly variable concentration to time profiles with multiple peaks in most cases (Fig .1). Based on the pharmacokinetics and biopharmaceutics of the compound this phenomenon maybe attributed to enterohepatic recirculation (1), gastric emptying or other variations of intestinal motility (2) and to absorption complexities related to the fact that it is a weak acid belonging to BCS class II (3) with pH– and buffer capacity–dependent dissolution behavior (4). The objective of the present study was to develop a population pharmacokinetic model, describing Irbesartan disposition.
Methods: Plasma concentration (C) – time (t) data were obtained from a single dose, 2x2 bioequivalence study comparing two immediate release oral products containing 300mg Irbesartan in 32 male volunteers. Non-linear mixed-effect modeling was applied and a variety of models were tested in order to explore different number of compartments, absorption kinetics, gastric emptying and enterohepatic recirculation. Gastric emptying was modeled using lag times, pseudo-compartments, sinusoidal equations and delay differential equations (5). Enterohepatic recirculation was modeled using previously developed models (1). The co-existence of gastric emptying and enterohepatic recirculation affecting Irbesartan disposition was also investigated. Models tested were evaluated in terms of their physiological relevance and goodness-of-fit criteria. Several error models were evaluated, whereas occasion and treatment effects as well as age, height, weight and BMI were tested as potential covariates. The entire computational work was implemented in Monolix 2018R1.
Results: The disposition of Irbesartan was best described by a two-compartment model with first order absorption and elimination (Equations 1-6). Application of delay differential equations coupled with the first order absorption constant was the most appropriate way to model plasma oscillations due to absorption complexities (Fig. 2). The pharmacokinetic 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). No statistically significant co-variate explaining between subject variability was found among those explored. Application of a combined error model led to the optimum description of residual variability.
Conclusion: Using delay differential equations a population pharmacokinetic model able to describe multiple peaks arising from absorption problems was developed for Irbesartan. Delay differential equations can be very useful in pharmacokinetic population modeling enabling the description of complex absorption phenomena leading to multiple peaks in plasma profile. This is due to the fact that a dynamical system is described where the lag from administration to absorption co-exists with all the distribution and elimination processes producing oscillations, as a result it is necessary to incorporate past history in the differential equation model (6).
Vangelis Karalis– Assistant Professor, National and Kapodistrian University of Athens, Athens, Attiki, Greece