Integration of preclinical and clinical data with pharmacokinetic modeling and simulation to evaluate fexofenadine as a probe for hepatobiliary transport function

Abstract

Purpose: The suitability of fexofenadine as a probe substrate to assess hepatobiliary transport function in humans was evaluated by pharmacokinetic modeling/simulation and in vitro/in situ studies using chemical modulators.

Methods: Simulations based on a pharmacokinetic model developed to describe fexofenadine disposition in humans were conducted to examine the impact of altered hepatobiliary transport on fexofenadine disposition. The effect of GF120918 on fexofenadine disposition was evaluated in human sandwich-cultured hepatocytes (SCH). Additionally, the effect of GF120918, bosentan, and taurocholate on fexofenadine disposition in perfused livers from TR(-) Wistar rats was examined.

Results: Based on modeling/simulation, fexofenadine systemic exposure was most sensitive to changes in the hepatic uptake rate constant, and did not reflect changes in hepatic exposure due to altered hepatic efflux. GF120918 did not impair fexofenadine biliary excretion in human SCH. GF120918 coadministration significantly decreased Cl'(biliary) to 27.5% of control in perfused rat livers.

Conclusions: Simulations were in agreement with perfused liver data which predicted changes in fexofenadine systemic exposure primarily due to altered hepatic uptake. Fexofenadine is not a suitable probe to assess hepatic efflux function based on systemic concentrations. GF120918-sensitive protein(s) mediate fexofenadine biliary excretion in rat liver, whereas in human hepatocytes multiple efflux proteins are involved in fexofenadine hepatobiliary disposition.

Figure I

Model scheme depicting fexofenadine disposition in healthy humans. X_gut represents the amount of fexofenadine in the gut after an oral dose; K_absorb represents the first–order absorption rate constant; C_C represents the concentration of fexofenadine in the central compartment (systemic circulation) with volume V_C; K₁₂ represents the first–order rate constant for hepatic uptake; K₂₁ represents the first-order rate constant for hepatic basolateral efflux; X_liver represents the amount of fexofenadine in the liver; K_bile represents the first–order rate constant for biliary excretion; X_bile represents the amount of fexofenadine in bile; K_urine represents the first–order rate constant for urinary excretion; X_urine represents the amount of fexofenadine in urine.

Figure II

Mean fexofenadine disposition in healthy humans. The curves represent the best fit of the pharmacokinetic model based on the scheme depicted in Fig. I to the data obtained from Shimizu et al. (9). The plasma concentration-time profile (♦ solid line) and urinary excretion rate-time profile (▲ dashed line) are plotted on log-linear scale. Symbols represent actual data points while lines represent the best fit of the model to the data.

Figure III

Simulated percentage change from baseline in the AUC of the (A) plasma concentration-time profile, predictive of systemic exposure, and (B) hepatic mass-time profile, predictive of hepatic exposure, associated with perturbations in the hepatic uptake rate constant (K₁₂; solid bars), basolateral efflux rate constant (K₂₁; hatched bars) and biliary excretion rate constant (K_bile; open bars).

Figure IV

Data generated in perfused livers from Mrp2-deficient TR⁻ rats. (A) Bile flow rates, (B) Fexofenadine concentrations in outflow perfusate, and (C) Biliary excretion rates of fexofenadine in livers perfused with 0.5 µM fexofenadine (●), 0.5 µM fexofenadine without 5 µM taurocholate (□), 0.5 µM fexofenadine + GF120918 (△), and 0.5 µM fexofenadine + bosentan (◊). Perfusate buffer contained 5 µM taurocholate, unless otherwise noted. Data represent mean ± SD (n-3–4 per group).