Archive for December, 2010
Posted by James
At this point, it is essential to determine whether the duration of drug therapy is sufficient for the patient to benefit from clinical pharmacokinetic monitoring.
The appropriate duration of therapy for voriconazole or any antifungal agent for an invasive fungal infection is not well established. Given the high mortality and morbidity associated with fungal infections, and the inherent difficulty of eradicating fungal pathogens, treatment of such infections may last from weeks to months, depending on the type of pathogen, the site and extent of the infection, and the patient’s immune status. For invasive pulmonary aspergillosis, the recommended treatment duration is a minimum of 6 to 12 weeks, whereas chronic pulmonary aspergillosis may require treatment with voriconazole for several months. Rarely would a patient be receiving voriconazole for less than 2 weeks, especially given that empiric therapy with voriconazole in febrile neutropenia is not recommended. In summary, if TDM is indicated (as determined by earlier steps in the algorithm shown in Figure 1), the duration of voriconazole therapy is adequate and appropriate to allow TDM to be performed and patient therapy to benefit.
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Posted by James
The next question to be answered is whether the drug has a narrow therapeutic range for the specific subpopulation (disease state) and specific indication.
Although some studies suggest a possible correlation between plasma concentration of voriconazole and efficacy, no break points in clinical response for efficacy and safety have been formally established. The suggested lower threshold for the therapeutic range varies from less than 0.25 mg/L to as high as 2 mg/L, and the upper threshold (to avoid toxic effects) varies from 4 to 6 mg/L.24,28,29,70 However, these threshold values should not be used routinely to guide dosing, since a causal relationship between plasma concentration of voriconazole and clinical response remains to be elucidated. Even if an association between concentration and efficacy or toxic effects does exist, the pharmacokinetic parameter that will best predict clinical response (Cmin, Cmax, or AUC) is unknown.
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Posted by James
At this point, it is important to reassess whether the relationship between concentration and pharmacologic response still applies to the patient’s specific subpopulation (disease state) and specific indication.
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Posted by James
The next question to be considered is whether the drug’s pharmacologic response is not readily assessable, in terms of both efficacy and toxic effects.
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Posted by James
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.
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Posted by James
The third consideration in deciding on TDM for voriconazole is whether a good relationship between drug concentration and pharmacologic response has been reported in pharmacokinetic studies conducted in humans.
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Posted by James
The use of voriconazole in pediatric patients has been described in several case reports and observational studies. In one study, treatment success (as determined by clinical, radiographic, and mycological evidence) was 45% among 58 children (ranging in age from 9 months to 15 years) with aspergillosis, candidiasis, or scedosporiosis. Cesaro and others conducted 2 small observational studies in pediatric patients with invasive fungal infections. In the first of these studies, 7 of the 8 patients had a response to voriconazole given as rescue or maintenance therapy. In the second study, 5 of 7 patients with invasive aspergillosis had a response to treatment with voriconazole. Kolve and others studied 37 immuno- compromised pediatric patients with invasive fungal infections and found that 86% of the patients with probable or proven infections and 100% of those with possible infections had a response to treatment and their condition remained stable. In a case series involving patients with cystic fibrosis and recurrent allergic bronchopulmonary aspergillosis, Hilliard and others reported a response to voriconazole therapy.
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