Quantitative management of the interaction of ritonavir on itraconazole plasma levels

L. Chouchana, I. Pierre, V. Poinsignon, E.M. Billaud*, L. Weiss

Author address: 

Paris, FR)

Abstract: 

Objectives: Itraconazole (ITZ) is an antifungal agent extensively metabolized by CYP3A4. It is largely involved in drug-drug interactions (DDIs) as a potent enzymatic inhibitor. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, especially because of its very long elimination half-life, of about 40 hours. We describe here the TDM-based management of the effect of ritonavir on ITZ in a HIV patient. Methods: ITZ, and its biologically active metabolite hydroxylitraconazole (OH-ITZ), plasma concentrations are assayed by a HPLC-Fluorometry method. ITZ dosage was adjusted to maintain trough levels (C0) of (ITZ + OH-ITZ) sum in the range of 1-1.50 mg/L. Results: A 40-year old HIV-infected patient admitted at the Infectious Disease department exhibited skin injuries due to a disseminated Penicillium marneffei infection. After 2 weeks of intravenous amphotericin B, oral ITZ 400 mg/day is introduced (day 0). At steady-state (day 10), ITZ and OH-ITZ through levels were, respectively, 1.00 and 1.30 mg/L (sum 2.30 mg/L). Later on, in the light of general clinical improvement and skin injuries resolution, a highly active antiretroviral therapy (HAART), including darunavir/ ritonavir 600 mg/100 mg bid, is started on day 109. A plasma assay realized 10 days after reveals that ITZ plasma level dramatically raised to 4.80 mg/L, associated to an extensive metabolism blockade with OH-ITZ at 0.70 mg/L. A dose reduction of daily ITZ intake by 2-fold (200 mg/day), did not prevent extremely high plasma levels of ITZ and OH-ITZ, respectively at 9.65 and 1.08 mg/L. Under TDM, ITZ was stopped for 36 days and elimination half-life was assessed to be increased at 17 days. ITZ has been reintroduced at a reduced dosage of 50 mg twice weekly, which has resulted in ITZ and OH-ITZ trough
2012

abstract No: 

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Full conference title: 

22nd European Congress of Clinical Microbiology and Infectious Diseases
    • ECCMID 22nd (2012)