Role of Therapeutic Drug Monitoring: Relation Between Concentration and Toxic Effects

Several studies and case reports have documented adverse effects potentially attributable to high concentrations of voriconazole in the plasma. Some of these studies are summa­rized in Table 2. The most frequently observed toxic effects of voriconazole are mild, such as headache, nausea, and vomiting, as well as elevated liver function tests, visual disturbances, and neurologic disturbances. The latter 3 adverse events have been suggested to correlate with plasma concentrations of voriconazole and are discussed in the next section.

In the study by Denning and others, 6 of 22 patients with random plasma concentrations of voriconazole above 6 mg/L had elevated results on liver function testing or liver failure requiring discontinuation of therapy, per study protocol. The authors suggested that the death of one patient was attributable to a high plasma concentration of the drug (> 13.9 mg/L). Six other patients had plasma concentrations above 10 mg/L, and 5 of these experienced adverse events requiring discontinuation of therapy; however, it was not clear whether the adverse events were caused by the voriconazole. Elevated results on liver function testing were also observed in the study by Trifilio and others, who found a positive correlation between concentrations of voriconazole and of aspartate aminotransferase (AST) and alkaline phosphatase (AP) (r = 0.5, p = 0.0009). However, no significant correlation was found with alanine aminotransferase (ALT), bilirubin, or creatinine. Pfizer’s pooled analysis of 10 therapeutic trials revealed an association between concentration of voriconazole and AST, AP, and bilirubin, but not ALT. The authors concluded, however, that routine monitoring of voriconazole concentration to prevent elevated liver function was unlikely to add any clinical value relative to regular monitoring of liver function while patients were receiving voriconazole. Interest­ingly, 3 other studies did not reveal any association between concentration of voriconazole and liver function. Viagra Soft Tabs



An association between elevated voriconazole concentra­tion and visual disturbances (including enhanced or altered visual perception, blurred vision, changes in colour vision, and photophobia) was also observed in Pfizer’s pooled analysis. Again, the authors concluded that routine monitoring of voriconazole concentrations is not warranted, despite the statistically significant positive correlation. This conclusion was based on the premise that visual disturbances represent, in general, a transient and mild effect that rarely necessitates discontinuation of voriconazole therapy.

Two trials reported a possible association between high concentration of voriconazole and neurologic adverse events. Pascual and others recorded neurologic events (including confusion, agitation, pattern of toxic encephalopathy on electroencephalography, extrapyramidal signs, myoclonus, and visual and auditory hallucinations) in 5 of the 16 patients who had trough concentrations of voriconazole above 5.5 mg/L; they observed no such effects in the group with concentrations of 5.5 mg/L or below (p = 0.002). In a small retrospective study, 4 of 6 patients with neurologic adverse events (including neuropathy, hallucinations, anxiety, insomnia, irritability, and impaired concentration) had trough concentrations of voriconazole above 4 mg/L. This correlation was significant, with a hazard ratio of 2.27 per 0.1 mg/L increase in trough concentration (95% CI 1.45-3.56,p < 0.001).
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To date there is insufficient evidence to establish a definitive relation between concentration of voriconazole and pharmacologic response, in terms of either efficacy or toxic effects. Although some studies have suggested a high likelihood of therapeutic failure with low concentrations of voriconazole, the break point in the clinical response is unclear, if indeed one exists. Also, it is unknown which pharmacokinetic parameter is the best predictor of response. Many of the studies discussed above used trough concentrations of voriconazole as a bench­mark, whereas some others used random concentrations or Cmax values. Evidence also suggests a possible correlation between high concentrations of voriconazole and toxic effects. These studies, however, had substantial shortcomings. Further­more, the clinical significance of such a relation must be considered, if one does exist. As Tan and others pointed out, routine TDM of voriconazole to prevent elevation of liver function and visual disturbance has minimal impact in therapeutic decision-making in the clinical setting. Conversely, as suggested by Imhof and others and by Pascual and others, TDM may be warranted in cases of neurologic adverse events caused by high concentrations of voriconazole. Nevertheless, the potential causal association and a clinically relevant target concentration must be established to guide clinical practice.
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Category: Drugs

Tags: antifungal, invasive fungal infection, pharmacokinetics, therapeutic drug monitoring, voriconazole

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