Voriconazole therapeutic drug monitoring – external evaluation of pharmacokinetic model predictive performance (poster)

MARKOVÁ, Eliška, Kateřina HORSKÁ and Šárka KOZÁKOVÁ. Voriconazole therapeutic drug monitoring – external evaluation of pharmacokinetic model predictive performance (poster). In 21st Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology. 2023.

Basic information

• Original name: Voriconazole therapeutic drug monitoring – external evaluation of pharmacokinetic model predictive performance (poster)
• Authors: MARKOVÁ, Eliška, Kateřina HORSKÁ and Šárka KOZÁKOVÁ.
• Edition: 21st Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, 2023.

Other information

• Type of outcome: Conference abstract
• Confidentiality degree: is not subject to a state or trade secret

Abstract

1. Introduction Voriconazole is a second-generation triazole antifungal primarily used as a first-line treatment for Aspergillus spp. infections with wide inter- and intra- individual variability in pharmacokinetics. Therefore, TDM of voriconazole should be performed for most patients. To perform TDM in routine clinical practice and fully use its potential, precise and possibly subpopulation-specific pharmacokinetic models are required. Our study aims to assess the interindividual variability in voriconazole pharmacokinetics, target specific subpopulations of patients, and identify relevant comorbidities affecting apparent pharmacokinetic variability. Correspondingly, we aim to evaluate the predictive performance and reliability of the currently available pharmacokinetic model. 2. Materials and Methods An external evaluation study cohort of 30 patients treated with voriconazole at University Hospital Brno. Data collected: measured voriconazole plasma levels, descriptive patient data, and basic biochemical and hematological parameters. Data were analyzed in the context of the target reference range, and the prediction error of the voriconazole pharmacokinetic model (voriconazole_C2_v2 model, MWPharm Online, Mediware a.s., version 1.7.6.0) was assessed. Prediction error was calculated as the difference between the predicted voriconazole level and the corresponding measured level. 3. Results From all of the voriconazole levels measured at a steady state (n=72), only 63% are within the target therapeutic range for voriconazole treatment (1,0 – 5,5 mg/l), 26% are subtherapeutic, 11% are supratherapeutic. Mean measured voriconazole level 2,75 mg/l (SD=5,98); voriconazole dosing is either on-label or higher. Nearly one-half of measurements are subtherapeutic when a minimal target through concentration is considered 2 mg/l, as recommended due to rising Aspergillus spp. resistance. On-label voriconazole dosing frequently leads to subtherapeutic measured levels (below 1,0 mg/l) – in nearly 40% of the cases. Based on our clinical experiences and preliminary results, the inter (and even intra-)- individual variability in voriconazole pharmacokinetics is high. The effect of the C-reactive protein and body weight on voriconazole levels, recently discussed in the literature, is also assessed in our study. These variables show a considerable impact on voriconazole levels; supratherapeutic voriconazole levels are most frequently measured in patients with a high level of CRP (> 100 mg/l). Moreover, we calculate the prediction error of the population pharmacokinetic model. In the initial phase, the mean prediction error is 3,43 mg/l (SD=2,13); minimal and maximal differences are 0,22 and 7,59 mg/l, respectively. After fitting, the mean predictive error is lower - 2,81 mg/l (SD=1,57). More than half of the predictions are considerably higher than measured levels for both primary and fitted predictions. 4. Discussions and Conclusions These preliminary data confidently demonstrate the importance of routine voriconazole TDM and support the urgent need for precise and subpopulation-specific pharmacokinetic models for higher clinical utility of voriconazole TDM. Besides that, the data raise the question of standard dosing recommendation adjustments.