Does metabolite matter? Defining target itraconazole and hydroxy‐itraconazole serum concentrations for blastomycosis

Abstract

Background: Itraconazole is the recommended first-line treatment for mild-tomoderate blastomycosis and consolidation treatment of moderate-to-severe disease.Itraconazole is metabolised into three metabolites, including an active metabolite hydroxy-itraconazole. Literature provides little evidence indicating whether therapeutic drug monitoring targets should be based on itraconazole parent compound alone or a sum of itraconazole and hydroxy-itraconazole serum concentrations.Objectives: This study aims to compare clinical outcomes and adverse drug events (ADEs) of combined itraconazole and hydroxy-itraconazole concentrations versus itraconazole parent compound alone in patients with blastomycosis.Patients/Methods: This study was a retrospective cohort review of patients ≥18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole concentration. The primary outcome was rate of partial or complete treatment response across three patient groups: (1) Itraconazole parent compound >1.0 mcg/ml (parent), (2) parent compound <1.0 mcg/ml, but a combined itraconazole and hydroxy-itraconazole >1.0 mcg/ml (combined) and (3) failure to achieve a combined or parent concentration >1.0 mcg/ml (subtherapeutic) for >75% of the duration of itraconazole therapy.Results: A total of 80 patients were included (parent = 32, combined = 36, subtherapeutic = 12). No statistically significant difference was observed for rate of partial or complete treatment response (97% parent vs 94% combined, p = .99). Significantly higher mortality due to blastomycosis was observed in patients in the subtherapeutic group (0% parent vs 3% combined vs 25% subtherapeutic, p = .01). Conclusions:This study supports an itraconazole therapeutic target combining itraconazole and hydroxy-itraconazole >1.0 mcg/ml for blastomycosis treatment.

Histoplasmosis in Solid Organ Transplantation

“…In patients with oropharyngeal candidiasis, itraconazole serum concentrations <1.0 mcg/mL were associated with treatment failures [103]. A recent study has shown that subtherapeutic concentrations (<1.0 mcg/mL) of itraconazole and hydroxyitraconazole were associated with increased mortality in patients with blastomycosis [104]. It is unclear if a concentration above 1.0 mcg/mL of the parent drug (itraconazole) or a combination of parent drug + metabolite (Itraconazole/hydroxyitraconazole) is required for improved outcomes in the management of histoplasmosis.…”