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Predicting the Outcome of Voriconazole Individualized Medication Using Integrated Pharmacokinetic/Pharmacodynamic Model

ABSTRACT: Therapeutic drug monitoring is considered to be an effective tool for the individualized use of voriconazole. However, drug concentration measurement alone doesn’t take into account the susceptibility of the infecting microorganisms to the drug. Linking pharmacodynamic data with the pharmacokinetic profile of individuals is expected to be an effective method to predict the probability of a certain therapeutic outcome. The objective of this study was to individualize voriconazole regimens by integrating individual pharmacokinetic parameters and pathogen susceptibility data through Monte Carlo simulations The individual pharmacokinetic parameters of 35 hospitalized patients who received voriconazole were calculated based on a validated population pharmacokinetic model. The area under the concentration-time curve for free drug/minimal inhibitory concentration (fAUCss/MIC) > 25 was selected as the pharmacokinetic/pharmacodynamic (PK/PD) parameter predicting the efficacy of voriconazole. The cumulative fraction of response (CFR) of the target value was assessed. To verify this conclusion, a logistic regression analysis was used to explore the relationship between actual clinical efficiency and the CFR value. For the 35 patients, the area under the free drug concentration-time curve (fAUCss) was calculated to be 34.90 ± 21.67 mgh/L. According to the dualistic logistic regression analysis, the minimal inhibitory concentration (MIC) value of different kinds of fungi had a great influence on the effectiveness of clinical treatment. It also showed that the actual clinical efficacy and the CFR value of fAUCss/MIC had a high degree of consistency. The results suggest that it is feasible to individualize voriconazole dosing and predict clinical outcomes through the integration of data on pharmacokinetics and antifungal susceptibility.

SUBMITTER: Yang P

PROVIDER: S-EPMC8548711 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundVoriconazole (VRZ) is a second-generation triazole antifungal agent with broad-spectrum activity. It is available in both intravenous and oral formulations, and is primarily indicated for treating invasive aspergillosis. The most commonly used dose for adults is 4 mg/kg or 200 mg twice daily. VRZ presents nonlinear pharmacokinetics in adults, whereas drug-drug interactions and cytochrome P450 2C19 (CYP2C19) polymorphism are of great concern for VRZ. Because the liquid chromatography method has been widely used for measuring VRZ blood concentration, and target VRZ blood concentration has been recommended in some guidelines regarding efficacy and safety, therapeutic drug monitoring is considered as a useful tool for VRZ-individualized medication. Also, the CYP2C19 genotype test is available for guiding relevant drugs use in some health care facilities. Our objective was to develop an evidence-based practice guideline for VRZ-individualized medication.MethodsWe followed the latest guideline definition from the Institute of Medicine and referred to the World Health Organization handbook for guideline development. The guideline was initially registered in the International Practice Guidelines Registry Platform (IPGRP-2015CN001). The guideline is, in principle, targeted at all Chinese health care providers. The quality of evidence and strength of the recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method.ResultsTwenty-six recommendations were formulated regarding therapeutic drug monitoring, special groups of patients, drug safety, off-indication use, and drug-drug interactions. Of them, 12 were strong recommendations. Most quality of evidence was low, very low, or expert opinions.ConclusionsWe developed an evidence-based practice guideline for VRZ-individualized medication, which provided comprehensive and practical recommendations for health care providers. The development of the guideline exposed several research gaps to improve VRZ use.

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Predicting the Outcome of Voriconazole Individualized Medication Using Integrated Pharmacokinetic/Pharmacodynamic Model

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