Category: Clinical Pharmacology
Purpose: A population pharmacokinetic model has been developed for Irbesartan incorporating delay differential equations (Equations 1-6), in order to mathematically describe its highly variable absorption resulting in multiple peaks. The objective of the present study was to utilize the model developed in order to explore the impact of the time delay between administration and absorption on the pharmacokinetics and pharmacodynamics of Irbesartan. The impact of different doses was also investigated.
Methods: The pharmacokinetic (PK) model developed using 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. The PK model was coupled with a previously developed pharmacodynamic model in healthy volunteers, where as pharmacodynamic markers systolic (SBP) and diastolic blood pressure (DBP) were used (1). Pharmacokinetic parameters were derived from the modeling exercise while the pharmacodynamic parameters from literature. Simulations were performed using Simulx included in the R package mlxR (2). According to Aprovel ® SmPC three different doses of Irbesartan were explored, i.e. 75, 150 and 300mg (3). Based on the intersubject variability of time delay estimated through the pharmacokinetic modeling exercise the range of time lags explored were 0-2.3 hours. AUC and Cmax were calculate in each case through non-compartmental analysis performed with PKCA R package (4).
Results: Concentration to time, SBP to time and DBP to time mean profiles were generated for three different doses of Irbesartan. Irbesartan presents linear and dose proportional pharmacokinetics for doses up to 300mg (3), so as expected dose increase produced an analogous increase of Cmax and AUC (Table 1, Fig. 1). Regarding the pharmacodynamic effect no significant difference was noted among doses, except of the fact that there was a tendency for higher doses to promote a more prolonged effect (Fig. 1). Changing the time delay promoted significant differences in Irbesartan disposition (Table 1, Fig. 2). Indeed, increasing the time delay lead to higher Cmax and delayed Tmax, without however affecting AUC. Pharmacodynamics were not affected as maximum effect was of the same amplitude and noted at the same time point for all time delays tested.
Conclusion: Simulations were performed using a simple system of delay differential equations describing disposition of Irbesartan coupled with a pharmacodynamic model found in the literature describing its blood-pressure lowering effect. Irbesartan followed dose proportional pharmacokinetics that led to a slightly prolonged pharmacodynamic behavior with higher doses. Time delay constituting the past history between administration and absorption may significantly affect Irbesartan pharmacokinetics but not pharmacodynamics.
Vangelis Karalis– Assistant Professor, National and Kapodistrian University of Athens, Athens, Attiki, Greece