Itraconazole—Life in the Old Drug Yet
Abstract & Commentary
Synopsis: It is now possible to treat pulmonary aspergillosis safely and effectively by giving itraconazole parenterally for 14 days, then continuing therapy orally.
Source: Caillot D, et al. Clin Infect Dis. 2001;33:E83-90.
A series of 31 immunocompromised patients were given itraconazole intravenously (2 days at 400 mg/d, then 200 mg/d thereafter) for a median duration of 14 days followed by oral capsules (400 mg/d) for a median duration of 11 weeks to treat invasive pulmonary aspergillosis. A satisfactory response (complete or partial response) was achieved in 15 (48%), with another 6 (19%) showing stable disease. Itraconazole was well tolerated and there were no unexpected side effects. Trough plasma concentrations of at least 250 µg/L (considered the therapeutic level) were attained by day 7 of intravenous therapy in all 22 patients for which data were evaluable and in all patients and therapeutic levels were maintained after switching to oral capsules. The average duration of treatment was 45 days (ie, 6 weeks) and only 2 patients had a definite adverse drug reaction (a rash and the other rigors during infusion). Caillot and colleagues considered this regimen to be safe, well tolerated, and effective for treating invasive pulmonary aspergillosis.
Comment by J. Peter Donnelly, PhD
Itraconazole was first brought to the market in 1992 in capsule form but quickly failed to meet some expectations. Like its predecessor, ketoconazole, absorption was erratic but there was no parenteral form available nor did one seem likely to become available because a suitable solvent for this hydrophobic drug had yet to be found. Neither did the notion of attempting to treat a life-threatening disease among allogeneic haematopoietic stem cell transplant recipients, and those given intensive chemotherapy for leukemia exclusively with a capsule appeal, especially as these patients tend to refuse taking anything by mouth because of nausea and mucositis. This dampened enthusiasm for an otherwise promising drug that just couldn’t be given to the patient at the desired dose in the most efficient way. Five years later in 1997 the absorption problem was solved by the introduction of an oral solution and then, finally, 2 years later, in 1999, a parenteral form of the drug finally made it in the nick of time, 7 years after the initial launch of itraconazole and just 2 years before its patent expired. IV-oral switch antifungal therapy had arrived.
It was a long time coming but there now seems to be a real alternative to amphotericin B in one or another of its formulations for treating the devastating disease of invasive pulmonary aspergillosis. True, there is no large trial comparing this IV-oral switch regimen for treating probable invasive pulmonary aspergillosis and none is planned. The evidence for judging efficacy is based on small series such as that of Caillot et al. Yet, while numerically small, such studies do represent a year or more of experience since few centers see more than 10 probable cases of invasive pulmonary aspergillosis per year. Clearly, the evidence that itraconazole is effective in treating probable or proven invasive pulmonary aspergillosis is not of the highest level because of the lack of a proper randomised, controlled, trial comparing the drug with the gold standard amphotericin B. Nonetheless, an examination of the literature available shows efficacy rates for itraconazole of 40-70%, in the same range as reported for amphotericin B. However, unlike the polyene, and earlier versions of itself, itraconazole can now be given parenterally and orally offering the physician the one and only flexible regimen to date. The optimum duration of parenteral treatment is not known, but is probably closer to 14 than 7 days, and the duration of follow-up oral therapy has yet to be determined. Those physicians that have hitherto relied on starting amphotericin B treatment while the patient is in the hospital and then discharging him or her on oral itraconazole now have a simpler alternative. Just as important, this approach to managing invasive pulmonary aspergillosis has a good chance of becoming the standard of care, if not with itraconazole, then with another azole antifungal agent such as voriconazole.
Dr. Donnelly, Clinical Microbiologist, University Hospital, Nijmegen, The Netherlands, is Associate Editor of Infectious Disease Alert.