(M0930-10-63) Physiologically Based Pharmacokinetic (PBPK) Modeling of Fexofenadine and Assessment of Transporter DDIs of Fexofenadine with P-gp Inducers and Inhibitors

Purpose: Fexofenadine (FEX), a H1-receptor antagonist used in the treatment of allergic rhinitis and chronic idiopathic urticaria, undergoes minimal metabolism and transporters play a major role in its absorption and disposition. FEX is frequently used as a probe substrate for P-gp, which plays a significant role in the apical efflux in the intestine, liver and kidneys. FEX is also a substrate for OATP2B1 uptake transporter, which is relatively highly expressed in the apical membrane of enterocytes, and a renal uptake transporter OAT3. The purpose of this project was to develop a PBPK model for FEX which accounts for all the relevant mechanisms impacting FEX pharmacokinetics (PK) after IV and PO administration in healthy Caucasian and Japanese subjects. This model was then validated by predicting the effect of P-gp inducers and inhibitors Rifampicin (RIF), Itraconazole (ITZ), and Verapamil on FEX PK.

Methods: The PBPKPlus^TM module in GastroPlus® v.9.8.2 was used to model the PK of FEX. The Advanced Compartmental Absorption and Transit (ACAT^TM) model was used to describe the intestinal absorption and dissolution of FEX after PO administration. Human physiologies were generated by the program’s internal Population Estimates for Age-Related Physiology (PEAR Physiology^TM) module. The systemic distribution of FEX was described using a whole body PBPK model with a permeability-limited model for kidney and muscle and a perfusion-limited model for the remaining tissues. Tissue/plasma partition coefficients were calculated from tissue composition and compound physiochemical properties using the default methods (Lukacova for perfusion-limited and Poulin and Theil -extracellular for permeability-limited tissues). The permeability-surface area products (PStc) for tissues described by a permeability-limited model were calculated from Specific PStc (Spec.PStc) value (PStc per mL of tissue cell volume) and the individual tissue cell volumes. The Spec.PStc (6x10^-4 mL/s/mL tissue) was fitted against data from an IV and oral microdose study¹ to correctly capture the tissue distribution. The P-gp efflux was modelled using built-in P-gp expressions in the liver, kidney, and individual intestinal compartments ^2,3. The influx due to OATP2B1 in gut was modeled using the expression levels obtained from literature⁴. The renal uptake due to OAT3 was modeled using built-in expression levels. The experimental in vitro K_m values for P-gp, OATP2B1, and OAT3 were taken from the literature ^5,6,7. The Vmax values for P-gp and OATP2B1 were optimized against the C_p-time profiles and the urinary excretion data after FEX 100 µg single dose administered IV and PO¹and the Vmax value for OAT3 was obtained from literature⁷. To capture reported saturation of P-gp impact on FEX absorption at therapeutic doses ⁸, the published in vitro K_m value for P-gp was reduced by 20% in the final model. To account for the OATP2B1 polymorphic effect in Japanese subjects, an influx V_max scale factor of 0.85 was used⁹. The DDI module in GastroPlus was used to predict the effect of RIF, ITZ, and Verapamil on FEX PK for varying study designs^10-16. Table 1 summarizes the induction and inhibition parameters for perpetrator drugs used in the DDI simulations.

Results: Figure 1 the Cmax and AUC predictions of clinical studies used as part of model development. The model accurately captures FEX PK after single and multiple dose administrations of doses ranging from 0.1 mg to 800 mg, with more than 70% of the predicted Cmax and AUC values within 25% of the observed data and 95% of predictions within 50% of the observed data ^{1,8, 17-20} . FEX C_P‑time profiles before and during co-administration with interacting drugs are also reasonably well predicted over the full range of administered doses and protocols. The predicted Cmax and AUC ratios are mostly within the Guest limits²¹ as shown in Figure 2. It is worthwhile to notice the Riff impact, which depending on the timing of FEX and RIF administration may show a net induction effect (ratio < 1) or net inhibition effect (ratio > 1) and model accurately captured these scenarios (orange points in in Figure 1).

Conclusion: The work aimed to develop the FEX PBPK model and validate it as a sensitive substrate model for use in predicting the potential DDI interactions between FEX and P-gp perpetrators. The PBPK approach incorporates all the relevant processes in drug ADME, and all the perpetrator mechanisms. The overall results presented in Figure 1 show that the model accurately predicts the interaction effect PO doses of FEX and perpetrators and the FEX model can be used to evaluate potential DDI interactions with other P-gp perpetrators.

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