Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases

Abstract

Aims: The gene polymorphism of voriconazole metabolism–related liver enzyme is notable in East Asia population. It casts a significant influence on the rational use of voriconazole. We conducted this study to investigate the relationship between steady-state voriconazole trough concentration (Ctrough) and adverse effects (AEs), especially hepatotoxicity. Methods: We conducted a real-world study in the Jinling Hospital from January 2015 to June 2020. A total of 140 patients receiving voriconazole were enrolled in this study. The determination and scoring of voriconazole-associated hepatotoxicity were performed according to the Roussel Uclaf Causality Assessment Method scoring scale and the severity of hepatotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: Elevated steady-state voriconazole Ctrough with concomitant AEs are the most common reason for dose adjustments during treatment. Compared with the group without any AEs, voriconazole Ctrough was significantly higher in the hepatotoxicity and neurotoxicity groups, and the incidence of both events showed an overall increasing trend with increasing voriconazole Ctrough. Hepatotoxicity occurred in 66.7% of patients within 7 days of the first dose of voriconazole and 94.4% within 15 days of the dose. Steady-state voriconazole Ctrough >3.61 mg/l was associated with an increased incidence of hepatotoxicity (area under the curve = 0.645, p = 0.047). Logistic regression analysis showed that timely voriconazole dose adjustment was a predictor of attenuated hepatotoxicity after adjustment for confounders, but hepatotoxicity was not associated with voriconazole Ctrough measured at a single time point. Conclusion: Hepatotoxicity and neurotoxicity correlate with voriconazole Ctrough, and dose reduction in patients with elevated steady-state voriconazole Ctrough may prevent hepatotoxicity. In patients with early occurrence of hepatotoxicity, initial therapeutic drug monitoring (TDM) might predict the risk of hepatotoxicity. Follow-up TDM may be necessary to predict late onset hepatotoxicity. Plain Language Summary Safety of voriconazole for the treatment of pulmonary fungal diseases Introduction: Several studies have suggested an association between the concentration of voriconazole in the blood and liver damage, but the evidence is weak. This study aimed to investigate relationships between voriconazole drug concentration and side effects and to analyze the factors affecting liver damage caused by voriconazole. Methods: We conducted a study at the Jinling Hospital from January 2015 to June 2020, in which a total of 140 patients were finally enrolled. Results: Voriconazole doses were adjusted in 44 patients due to abnormal voriconazole drug concentration or side effects, 32 patients reduced the dose and 8 patients increased the dose. An elevated liver enzyme level was the most common cause for dose adjustment. After the first dose adjustment, most patients achieved the target drug concentration. A total of 18 patients were determined as probable or highly probable to have drug-induced liver injury from voriconazole. Voriconazole drug concentration was significantly higher in the liver damage and nervous system damage groups as compared with the group without any side effects, and most liver damage events occurred within 14 days of the first dose. Voriconazole drug concentration >3.61 mg/l was associated with an increased incidence of liver damage. Conclusion: In this study, approximately one-third of patients with pulmonary fungal disease needed to adjust their dose after the standard dose of voriconazole treatment. The incidence of liver damage and nervous system damage showed an overall increasing trend with increasing voriconazole baseline concentrations. Initial therapeutic drug monitoring may be predictive of liver damage. Follow-up monitoring of liver enzymes may be needed.

Voriconazole trough concentration and clinical outcomes in patients with Talaromycosis

“…The main AEs related to VRC were neurotoxicity and hypokalemia, which may lead to a risk of discontinuation. In contrast to previous studies [21,22] , we did not observe liver and kidney function damage in talaromycosis patients treated with VRC. When neurotoxicity and hypokalemia occurred, these AEs quickly disappeared after clinical disposal or replacement of the antifungal regimen and were similar to previous observations [14] .…”

Development of a therapeutic drug‐monitoring algorithm for outpatients receiving voriconazole: A multicentre retrospective study

“…Regarding initial TDM, a previous study reported that 45.5% of patients had their VRCZ dose adjusted at the first measurement, and inappropriate VRCZ trough concentrations were the most common reasons for the first dose adjustment. 28 In our study, 50% of VRCZ trough concentrations at the first measurement in the treatment and prophylaxis groups were abnormal, therefore the first measurement (treatment, days 3-5 after the initiation of VRCZ therapy; prophylaxis, days 5-8)…”

“…This might be because there are no opportunities for physicians and pharmacists to monitor clinical symptoms or laboratory data frequently. Regarding initial TDM, a previous study reported that 45.5% of patients had their VRCZ dose adjusted at the first measurement, and inappropriate VRCZ trough concentrations were the most common reasons for the first dose adjustment 28 . In our study, 50% of VRCZ trough concentrations at the first measurement in the treatment and prophylaxis groups were abnormal, therefore the first measurement (treatment, days 3‐5 after the initiation of VRCZ therapy; prophylaxis, days 5‐8) and long‐term prescriptions for prophylaxis could be better timed to conduct TDM for outpatients.…”

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

“…Furthermore, risk-benefit analysis should be performed in combination with the patient's actual situation. 41,42 In addition, in this study, we used fAUC/MIC > 25 as the PK/PD index; it should be noted, however, that when AUC/MIC is used as a predictor, its target value should also be adjusted. 43 The current study has several limitations that need to be considered.…”

“…Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions. Furthermore, risk‐benefit analysis should be performed in combination with the patient's actual situation 41,42 . In addition, in this study, we used f AUC/MIC > 25 as the PK/PD index; it should be noted, however, that when AUC/MIC is used as a predictor, its target value should also be adjusted 43 …”