Abstract
Introduction: Itraconazole (ITZ) is a BCS Class II triazole antifungal (Sporanox; Janssen Pharmaceutica, Titusville, NJ). It is a substrate and potent inhibitor of CYP3A4. The primary metabolite hydroxy-itraconazole (OH-ITZ) and the two other downstream metabolites, ketoitraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ), are also substrates and inhibitors of CYP3A4. The purpose was to develop a mechanistic absorption model (MAM)/PBPK model for ITZ and its metabolites which accounts for all the relevant mechanisms (dissolution, precipitation, absorption, distribution, metabolism, and auto-inhibition) after i.v. and p.o. ITZ administration.. This model was validated by predicting effect of ITZ administration on midazolam (MID) pharmacokinetics (PK).
Methods: The PBPKPlus™ module in GastroPlus™ (Simulations Plus, Inc.) was used to model the PK of ITZ and the three metabolites. The Advanced Compartmental Absorption and Transit (ACAT™) model was used to describe the intestinal dissolution, precipitation, and absorption of ITZ after p.o. administration. Human physiologies were generated by the program’s internal Population Estimates for Age-Related (PEAR™) Physiology™ module. Tissue/plasma partition coefficients for all the compounds were calculated using the Lukacova algorithm based on tissue composition and in vitro and in silico physicochemical properties. The biopharmaceutical parameters for both ITZ and its metabolites were either obtained from literature or predicted by ADMET Predictor™ 6.5 (Simulations Plus, Inc.). The metabolism series from ITZ to OH-ITZ to keto-ITZ to ND-ITZ (all mediated by the CYP3A4 enzyme) was modelled by Michaelis-Menten kinetics with in vitro enzyme kinetic parameters and the GastroPlus built-in expression levels of CYP3A4 in gut and liver. The default dissolution model was used for both solution and capsule dosage forms. Particle size for the capsule dosage form was adjusted to 3 μm to account for the formulation effect. The program’s mechanistic nucleation and growth (MNG) model was used to account for possible precipitation as ITZ solubility changes in different intestinal regions. The permeability of ITZ was predicted in MembranePlus™ 1.0 (Simulations Plus, Inc). The DDI module in GastroPlus was used to predict the effect of ITZ on MID PK for a variety of study designs (varying ITZ and MID doses and administration times).
American Association of Pharmaceutical Scientists (AAPS), October 25-29, 2015, Orlando, FL
By Ke X. Szeto, Viera Lukacova, John DiBella, Walter S. Woltosz, and Michael B. Bolger