Eunsol Yang, PhD (1), Jae-Yong Chung, MD, PhD (2), SeungHwan Lee, MD, PhD (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, (2) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
Objectives: Abnormal gastric acidity including achlorhydria can act as a significant source of variability in the absorption of drugs especially with pH-sensitive solubility profiles, potentially resulting in an undesirable therapeutic response [1]. Physiologically based pharmacokinetic (PBPK) modeling is an emerging tool for quantitatively evaluating drug exposure in terms of gastric pH on a mechanistic basis of the drug’s physicochemical properties, such as solubility and dissolution [2]. However, to date, there is limited experience with the use of PBPK modeling for predicting gastric pH-mediated drug exposure changes [3]. Itraconazole is a biopharmaceutics classification system class II weak base drug with an extremely poor and pH-dependent solubility profile [4]. Previous studies have reported that the absorption of itraconazole was impaired and varied under low gastric acidity induced by acid reducing agent (ARA) [5-6]. This study was aimed to explore the utility of PBPK modeling in quantitative prediction of gastric pH-mediated drug exposure changes by using itraconazole as a case drug.
Methods: A PBPK model for itraconazole was constructed using the diffusion layer model (DLM) within the Advanced Dissolution, Absorption and Metabolism model to quantify dissolution and absorption profiles according to gastric pH. Mechanistic absorption kinetics was modeled by a stepwise in vitro-in vivo extrapolation approach, by which absorption parameters (e.g. solubility factor, bile micelle partition coefficient) were calculated or estimated from in vitro pH-dependent solubility and dissolution data. Furthermore, the parameters, DLM scalar and particle radius, were optimized towards clinical data under normal gastric acidity [7]. The predictive performance for gastric pH-mediated pharmacokinetic (PK) variability of the model was then validated using independent clinical data under normal gastric acidity and ARA-induced achlorhydria; gastric pH was reflected as the observed physiological values in the absence or presence of ARA, which were 1.9 for fasted and 4.9 for fed under normal gastric acidity, and 5.0 for fasted under induced achlorhydria [6, 8]. The final model was subsequently applied to virtual achlorhydric populations to quantitatively predict gastric pH-mediated exposure changes; gastric pH was adjusted to 5.7 for fasted and 6.4 for fed by setting an achlorhydria frequency of 100%. Sensitivity analyses were conducted to explore the impact of gastric pH on the absorption and systemic exposure of itraconazole. PBPK modeling and simulation were conducted using Simcyp® Simulator version 20.0, and modeling with in vitro experimental data was performed using Simcyp In Vitro data Analysis toolkit version 4.0.
Results: The developed PBPK model for itraconazole reasonably reproduced not only PK profiles under normal gastric acidity and induced achlorhydria but gastric pH-mediated exposure changes. In achlorhydric populations, the predicted fraction absorbed of itraconazole was reduced by 42% at fasted state and 31% at fed state, thereby decreasing the predicted systemic exposure of itraconazole up to 59% at fasted state and 31% at fed state, than in populations with normal gastric acidity. Sensitivity analyses showed that gastric pH elevation had a more pronounced impact on itraconazole PK at fasted state than at fed state, indicating less sensitivity to gastric pH due to bile salt-enhanced solubility after food intake. The model-based simulations mechanistically interpreted that gastric pH-mediated exposure changes of itraconazole were ascribed to sequential variation in total solubility, dissolution, and absorption according to gastric pH alteration.
Conclusions: This study suggested the utility of PBPK modeling in quantitative prediction of gastric pH-mediated exposure changes, especially for drugs whose absorption is susceptible to gastric pH variation. Our findings will serve as a foundation for further mechanistic assessment of exposure changes in terms of gastric pH for other drugs, ultimately contributing to personalized pharmacotherapy.
References:
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[2] Kaur, N., A. Narang, and A.K. Bansal, Use of biorelevant dissolution and PBPK modeling to predict oral drug absorption. Eur J Pharm Biopharm, 2018. 129: p. 222-246.
[3] Zhang, X., et al., Application of PBPK Modeling and Simulation for Regulatory Decision Making and Its Impact on US Prescribing Information: An Update on the 2018-2019 Submissions to the US FDA’s Office of Clinical Pharmacology. J Clin Pharmacol, 2020. 60 Suppl 1: p. S160-s178.
[4] Ghazal, H.S., et al., In vitro evaluation of the dissolution behaviour of itraconazole in bio-relevant media. Int J Pharm, 2009. 366(1-2): p. 117-23.
[5] Jaruratanasirikul, S. and S. Sriwiriyajan, Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol, 1998. 54(2): p. 159-61.
[6] Lange, D., et al., Effect of a cola beverage on the bioavailability of itraconazole in the presence of H2 blockers. J Clin Pharmacol, 1997. 37(6): p. 535-40.
[7] Lee, J. and Cho, J.Y., unpublished data, 2014.
[8] Yang, E. and Lee, S., unpublished data, 2022.
Reference: PAGE 30 (2022) Abstr 9972 [www.page-meeting.org/?abstract=9972]
Poster: Drug/Disease Modelling - Absorption & PBPK