Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations

Area of Science:

• Pharmacology
• Mycology
• Clinical Medicine

Background:

• Itraconazole is an oral triazole antifungal agent with broad-spectrum activity, including against Aspergillus species.
• Its use for prophylaxis of aspergillosis in neutropenic patients has increased.
• Neutropenic patients, particularly those with hematologic malignancies, are at high risk for invasive fungal infections.

Purpose of the Study:

• To evaluate the variability of itraconazole plasma concentrations in neutropenic patients undergoing chemotherapy.
• To determine if standard dosing achieves therapeutic drug levels in this patient population.
• To assess the need for therapeutic drug monitoring of itraconazole in neutropenic patients.

Main Methods:

• Retrospective analysis of 74 trough itraconazole concentrations at steady state in 16 patients with acute myeloid leukemia or malignant lymphoma.
• Patients received daily itraconazole doses ranging from 400-600 mg.
• Intra-individual variability was assessed in six patients receiving 600 mg/day during chemotherapy.

Main Results:

• Therapeutic itraconazole concentrations (≥1000 ng/ml) were not achieved in 31% of patients.
• Consistent therapeutic levels were obtained in only 19% of patients on standard dosing.
• Plasma levels varied up to 15-fold between patients on the same dose and significantly within individuals (-53% to +245%).

Conclusions:

• Significant inter-patient and intra-individual variability in itraconazole plasma concentrations exists in neutropenic patients.
• Standard itraconazole dosing (400-600 mg/day) is often insufficient to achieve therapeutic levels.
• Therapeutic drug monitoring of itraconazole is essential for neutropenic patients to ensure effective prophylaxis against aspergillosis.