(M1430-07-40) Mechanistic PBPK Modelling of Itraconazole Oral Solutions: Evaluating HP-β-CD Impact on Solubility and Drug-Drug Interactions

Purpose: Excipients, such as cyclodextrins, are routinely employed in pharmaceutical formulations, particularly for enhancing the solubility of poorly soluble drugs through the formation of inclusion complexes. However, the binding of drug molecules to cyclodextrin molecules leads to a decrease in unbound drug concentration, thereby reducing absorption rate into the gut wall. Notably, Itraconazole Oral Solution, marketed under the brand name Sporanox®, is formulated with hydroxypropyl-β-cyclodextrin (HP-β-CD). While initially intended as an antifungal medication, it is currently also utilized as a potent cytochrome P450 3A (CYP 3A) inhibitor in various drug-drug interaction (DDI) studies. In this research work, we present a PBPK model for Sporanox Itraconazole Oral Solution utilizing the Simcyp Simulator V23. It evaluates the effect of HP-β-CD on the pharmacokinetics of the Itraconazole solution and investigates the solubility-permeability interplay.

Methods: Due to the differential affinities of various drugs to cyclodextrins, competitive interactions may occur between co-dosed oral drug products, resulting in the formation of new inclusion complexes. This phenomenon can significantly impact the absorption of drugs co-administered with Itraconazole (Durk et al., 2020). To examine this intricate interplay, a physiologically based pharmacokinetic (PBPK) model has been developed to mechanistically account for the effects of the excipients on the dissolution and absorption of active pharmaceutical ingredients. The model incorporates solubility enhancement of drugs through binding to cyclodextrin and the formation of inclusion complexes. The SIVA 5 toolkit has been utilized to estimate the drug to cyclodextrin binding constants based on the solubility experiments of Itraconazole using various concentration of HP-β-CD at different pH values, as reported by Peeters et. al. (2001). The PBPK model also dynamically tracks the concentration of cyclodextrin along the gastrointestinal tract such that solubilisation changes with time are modelled. Additionally, a mechanistic permeability model elucidates the repercussions of dynamic reduced free fractions on effective gut wall permeability and active pharmaceutical ingredient diffusivity.

Results: The Itraconazole PBPK model was initially developed as an inhibitor of the CYP3A4 enzyme and has been verified against steady-state clinical data for both fasted and fed states, as reported by Barone et al. (1998). Then the model was expanded accounting for the complex simultaneous metabolic and excipient-mediated DDIs of Itraconazole oral Solutions. Figure 1 shows the simulated concentration profiles in fasted and fed conditions compared against the observed data.

Conclusion: The PBPK model developed for Sporanox Itraconazole oral solution effectively elucidates the complex interplay between solubility enhancement by HP-β-CD and the reduced free fractions impacting gut wall permeability. The model's verification against clinical data under varying nutritional states confirms its robustness in simulating both metabolic and excipient-mediated drug-drug interactions. These findings underscore the critical role that excipients can play in modulating drug pharmacokinetics and highlight the importance of considering such interactions in the formulation and therapeutic use of pharmaceuticals.

References: 1) Matthew R. Durk,*, Nicholas S. Jones, Jia Liu, Karthik Nagapudi, Chen Mao, Emile G. Plise, Susan Wong, Jacob Z. Chen, Yuan Chen, Leslie W. Chinn and Po-Chang Chiang, Understanding the Effect of Hydroxypropylβ-Cyclodextrin on Fenebrutinib Absorption
in an Itraconazole–Fenebrutinib Drug–Drug
Interaction Study, 2020, Clinical Pharmacology & Therapeutics | Volume 108 Number 6
2) Joseph A. Barone, Pharm.D., Bruce L. Moskovitz, M.D., Joseph Guarnieri, Ph.D., Alan E. Hassell, M.S.,
John L. Colaizzi, Ph.D., Robert H. Bierman, M.D., and Lois Jessen, Pharm.D., Food Interaction and Steady-State Pharmacokinetics of
Itraconazole Oral Solution in Healthy Volunteers, 1998, Pharmocotherapy Volume 18, Number 2
3) JEF Peeters, Peter Neeskens, Jan P. Tollenaere, Pieter Van Remoortere, Marcus E. Brewster, Characterization of the Interaction of 2-Hydroxypropyl-bcyclodextrin With Itraconazole at pH 2, 4, and 7, 2002, Journal of Pharmaceutical Sciences, VOL. 91, NO. 6

Mean Values of Systemic Concentration in Plasma of Itraconazole, A) Fasted Solution, B)Fed Solution. Observed clinical data are as reported by Barone et al. (1998).