ArticleClinical pharmacokinetics2016
Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction.
Article in Clinical pharmacokinetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Sporothrix brasiliensis Treatment Failure without Initial Elevated Itraconazole MICs in Felids at Border of Brazil.Emerging infectious diseases · 2025Article
- Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions: Research Methods and Applications.Metabolites · 2023Review
- Physiologically-based pharmacokinetic modeling to evaluate in vitro-to-in vivo extrapolation for intestinal P-glycoprotein inhibition.CPT: pharmacometrics & systems pharmacology · 2022Article
- Prediction of the drug-drug interaction potential of the α1-acid glycoprotein bound, CYP3A4/CYP2C9 metabolized oncology drug, erdafitinib.CPT: pharmacometrics & systems pharmacology · 2021Article
- Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator.CPT: pharmacometrics & systems pharmacology · 2021Article
- Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model.Clinical pharmacokinetics · 2020Article
- Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib: Understanding Complex Drug-Drug Interactions.CPT: pharmacometrics & systems pharmacology · 2020Article
- Development and Evaluation of Physiologically Based Pharmacokinetic Drug-Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations.Pharmaceutics · 2019Article
- Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model.CPT: pharmacometrics & systems pharmacology · 2019Article
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Authors and funding
9 authors.
Funding
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Abstract
BACKGROUND AND
objectivesPhysiologically based pharmacokinetic (PBPK) modeling for itraconazole has been challenging due to highly variable in vitro d ata used for 'bottom-up' model building. Under-prediction of pharmacokinetics and drug-drug interactions (DDIs) following multiple doses of itraconazole has limited the use of PBPK model simulation to aid an itraconazole clinical DDI study design. The aim of this work is to develop an itraconazole PBPK model predominantly using a 'top-down' approach to enable a more accurate pharmacokinetic and DDI prediction.
methodsAn itraconazole PBPK model describing itraconazole and hydroxyl-itraconazole (OH-ITZ) was constructed in Simcyp(®). The key parameters that govern the pharmacokinetic profile, including non-linear clearance (i.e., maximum rate of reaction [V max] and the Michaelis-Menten constant [K m]) and volume of distribution for both itraconazole and OH-ITZ, were redefined by leveraging existing in vivo data. Model verification was performed by comparing the simulated itraconazole and OH-ITZ pharmacokinetic profiles with the observed clinical data. Finally, the model was used to simulate clinical DDIs between itraconazole and midazolam.
resultsThe developed PBPK model well-described the pharmacokinetics of itraconazole and OH-ITZ, and particularly captured their accumulation after repeated doses of itraconazole. This was verified with the observed data from 29 clinical studies where itraconazole solution or capsule was given as a single or multiple dose. The predicted DDI between itraconazole and midazolam was within 1.25-fold of the observed data for seven of ten studies and within 1.5-fold for nine of ten studies.
conclusionThe improvement of the itraconazole PBPK model increased our confidence in using PBPK model simulations to optimize clinical itraconazole DDI study design.
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