Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients

Sir, Systemic mycoses, such as invasive aspergillosis, are usually treated with antifungal drugs such as iv amphotericin B or itraconazole capsules. The plasma concentrations of itraconazole observed in patients are sometimes much higher than the minimal therapeutic level (1000 ng/mL), and the potential hepatic toxicity of the drug needs to be evaluated. A retrospective study on the effect of itraconazole on liver enzyme levels was conducted after checking bioavailability by plasma assays. Twenty patients, hospitalized between 1 January 1993 and 1 February 1998 were studied. Fourteen had leukaemia, four chronic respiratory insufficiency and one cystic fibrosis, while one had a lung transplant, all complicated by fungal ‘infections’ (12 definitely or probably had invasive aspergillosis, seven were colonized with an Aspergillus sp. and one had Scedosporium sp. sinusitis). Inclusion criteria were: a curative treatment by itraconazole followed by at least one serum concentration (out of three to six assays) 2500 ng/mL of unchanged itraconazole and of its active metabolite (total 5000 equivalent ng/mL). Patients with known hepatic illness before the start of itraconazole therapy, and those with a history of alcohol abuse, were excluded. Patients were treated for 44–455 days (median 143 days with itraconazole 200–600 mg/day (900 mg/day in two patients for 8 days). Twelve patients, all with leukaemia, received itraconazole and amphotericin B for 10–54 days (median 28 days). None of these patients received a bone marrow transplant. No disorders were observed in eight patients, even during the period of high plasma itraconazole concentration. One patient with liver dysfunction presented with cholecystitis at the onset of itraconazole therapy, which was resolved by surgery, but no subsequent hepatic disorders were seen. The 11 other patients, all with leukaemia, had increases in -glutamyltranspeptidase ( GT) and alkaline phosphatase (AP) (median value of 6.5 and 2.5 higher than the normal limit). In nine of these patients, ALT levels were also increased. In three patients such abnormalities were only seen during the period of high plasma itraconazole concentration, with a decrease following a decrease of itraconazole treatment. Different co-drugs were given to these 11 patients and their possible interactions were analysed by a causality assessment. Amphotericin B was the only drug administered, in addition to itraconazole, to all these 11 patients with hepatic disorders. Another leukaemic patient was also treated with itraconazole and amphotericin B, with no hepatic disorders. For the 12 patients treated with itraconazole and amphotericin B, the GT, AP and ALT concentrations were measured at three times: (i) before the beginning of antifungal therapy (period A), during administration of amphotericin B plus itraconazole (and within 21 days after amphotericin B treatment was ended, a time corresponding to seven halflives of the drug) (period B) and 2 months after the end of amphotericin B treatment (period C) (Figure). For each patient, hepatic enzyme concentrations were greatest during period B (Friedman test: P 0.001 for GT and AP, P 0.0015 for ALT). In seven patients, these abnormalities disappeared when amphotericin B was discontinued, although itraconazole therapy was continued. In three other patients, hepatic enzyme abnormalities were observed 5–19 days after the end of amphotericin B therapy. For one patient, the data for period C were not available. A significant increase in hepatic enzyme values, in 11 (92%) out of 12 leukaemic patients was seen. This increase appeared not to be related to the period of high plasma itraconazole concentration for eight of the patients but it was observed during simultaneous treatment with itraconazole plus amphotericin B or a few days after amphotericin B treatment ended.