Generic substitution of itraconazole resulting in sub-therapeutic levels and resistance
Author:
Pasqualotto AC, Denning DW
Date: 24 April 2007
Abstract:
Correspondence; no abstract. First paragraph: Itraconazole is a widely used oral antifungal drug for aspergillosis and superficial fungal infection (2004 UK community expenditure £4.4 million). However, the itraconazole capsule formulation is well known for its unpredictable bioavailability, hence the widespread adoption of drug-level monitoring in vulnerable and non-compliant patients. Variation in PK profiles is due not only to variable bioavailability but also to individual variation of cytochrome P450 activity. Extensive drug interactions can occur with itraconazole because it is both an inhibitor and substrate of the CYP3A4 enzyme and P-glycoprotein transporter systems. Although the use of generic drugs is encouraged in order to minimise health expenditure, here we report that three patients had significant problems after substitution of the generic formulation of itraconazole (Sandoz), including the development of antifungal resistance (Table 1). None of these problems was attributable to drug interactions. All itraconazole levels were performed with bioassay with a therapeutic range of 5.0-15.0 mg/L. It should be noted that the results obtained with bioassay are 2-10 times higher than the results obtained for HPLC, mainly because microbiological assay methods detect an active metabolite in addition to the drug itself (Table 1).
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