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European Experience With Oral Solution and Intravenous Itraconazole

European Experience With Oral Solution and Intravenous Itraconazole

ABSTRACT: The availability of an improved oral solution and an intravenous (IV) formulation of itraconazole (Sporanox) promises to have an effect on prevention and treatment of fungal infection in immunocompromised patients. Use of itraconazole in neutropenic patients with hematologic malignancies has been evaluated in a number of European studies. Treatment with IV followed by oral itraconazole resulted in response or stable disease in two-thirds of patients with invasive pulmonary aspergillosis. Empiric treatment with IV followed by oral solution itraconazole was at least as effective as, and significantly less toxic than, amphotericin B. Several studies of oral solution prophylaxis indicate effectiveness in prevention of fungal infection. Oral solution and IV itraconazole are useful in a variety of situations in prophylaxis, empiric therapy, and treatment of probable/confirmed infection. Itraconazole exhibits a broad spectrum of activity against Aspergillus and Candida species. It has potential advantages over fluconazole (Diflucan), which does not exhibit in vitro activity against Aspergillus and most non-albicans Candida species, and amphotericin B, which is associated with a high incidence of toxicity. Aggressive use of itraconazole and amphotericin B preparations in treatment of fungal infection at Royal Free Hospital may have reduced mortality associated with aspergillosis. [ONCOLOGY 15(Suppl 9):27-32, 2001]

Itraconazale (Sporanox) has been used in a number of
European studies in patients with neutropenia and hematologic malignancies.
These studies have shown that itraconazale has a promising effect in both the
prevention and treatment of fungal infection when administered intravenously
followed by oral doses.

Efficacy and Safety Study

In a multicenter, open-label, single- group study, Caillot and colleagues[1]
evaluated the efficacy and safety of itraconazole in 31 immunocompromised adult
patients with invasive pulmonary aspergillosis. Of the 31 patients participating
in the study, 90% had hematologic malignancy, 7% had graft-vs-host disease, and
3% had AIDS; 61% of the patients were neutropenic.

The study also assessed plasma levels of itraconazole and the active
metabolite hydroxy-itraconazole to determine the pharmacokinetics of the
intravenous (IV)/oral capsule dosing regimen that was used.

Aspergillosis was diagnosed on the basis of positive tissue biopsy, culture
or direct examination of percutaneous lung aspirate, presence of new or
progressive infiltrates on x-ray or computed tomography (CT) with positive
sputum or bronchoalveolar lavage or positive nasal swab (in neutropenic
patients), or when bronchoscopy/lavage and CT scans showed typical halo or air
crescent signs.

Dosage and Response

Treatment consisted of itraconazole IV at 200 mg twice daily for 4 days and
200 mg once daily for 12 days, followed by oral itraconazole capsules 200 mg
twice daily for 12 weeks. Outcomes were assessed at day 14 and at 14 weeks. All
31 patients received IV itraconazole for a median of 14 days, and 26 received
oral itraconazole for a median of 78.5 days.

Response (defined as resolution or major improvement in all signs and
symptoms) at day 14 was observed in 38% of patients, with response or stable
disease being observed in 81%. By the end of study treatment, response was
observed in 48% of patients, with response or stable disease being observed in
68%.

Plasma Drug Concentrations

Figure 1 shows plasma drug concentrations, assessed by high-performance
liquid chromatography with ultraviolet detection, during the course of the
Caillot study. Therapeutic trough plasma levels (> 250 ng/mL) were obtained
in 91% of the patients within 2 days of IV treatment and in all patients within
1 week of IV treatment. Therapeutic levels exceeding the minimum effective
concentration were maintained after changing from IV to oral treatment. In
total, adverse events were reported in 42% of patients during IV treatment and
35% during oral treatment. Treatment was discontinued due to adverse effects in
seven patients; two related to the IV preparation (rigors and rashes) and five
related to the oral preparation (gastrointestinal side effects).

Empiric Therapy in Neutropenic Patients

DeBeule and colleagues[2] performed a multicenter, open-label, randomized
study to assess the pharmacokinetics of an IV/oral solution itraconazole regimen
and to compare the effects of itraconazole and amphotericin B as empiric therapy
for fever of unknown origin in neutropenic patients with hematologic
malignancies.

Methods

The study enrolled a total of 394 adults with hematologic malignancies with
neutropenia (absolute neutrophil count < 500,000 × 10³/L) expected to last for 7
days and persistent fever (> 38°C) despite 3 to 7 days of broad-spectrum
antimicrobial treatment. A total of 384 patients received at least one dose of
study medication and were included for safety analysis. Evaluation of efficacy
was based on an intention to treat 360 randomized patients who satisfied the
full inclusion/exclusion criteria.

Underlying diagnoses were similar in the two treatment groups, with 56% of
patients in each having acute myelogenous leukemia (AML). The treatment groups
were well-matched for risk factors, with similar proportions of patients
undergoing first treatment or having first or second or subsequent relapse,
similar proportions undergoing autologous bone marrow transplantation (BMT) or
peripheral blood stem cell transplantation, and similar proportions using
corticosteroids, exhibiting fungal colonization of the digestive tract, and
exhibiting mucositis. The median duration of neutropenia was approximately 9
days in both groups.

Dosage and Response

Treatments consisted of itraconazole IV 200 mg twice daily for 2 days and 200
mg once daily for 5 to 12 days followed by oral solution 400 mg once daily from
day 15 to day 28 or amphotericin B IV at 0.7 to 1.0 mg/kg/d for 28 days.

Patients in the itraconazole group received IV treatment for a median of 8.5
days; 65 patients switched to oral itraconazole for a median of 7 days after a
median of 9 days of IV treatment. Patients in the amphotericin B group received
IV amphotericin B for a median of 7 days; the mean amphotericin B dose was 0.71
mg/kg/d.

Treatment response was defined as absence of fever for 3 days and a recovery
from neutropenia for a minimum of 2 consecutive days. Failure was defined as
documented deep fungal infection or highly suggestive CT findings, documented
bacterial or viral infection responsible for fever, death due to any cause
within 3 days of starting study treatment, persistent fever at the end of
neutropenia or at day 28, persistence of signs and symptoms of fungal infection
irrespective of presence of fever, fever requiring a change in the antifungal
regimen, or discontinuation of study medication due to poor tolerance.

Outcomes

In total, 24 (13%) of the itraconazole patients and 46 (25%) of the
amphotericin B patients were considered unevaluable on the basis of receiving
treatment for 3 or fewer days. Failure occurred in 72 (39%) and 70 (38%) of the
intraconazole and amphotericin B recipients, respectively, and response occurred
in 48% and 38%, respectively. It was calculated that itraconazole was at least
as effective as amphotericin B treatment (P = .001, Fleiss test).

A further analysis based on the composite end point[3] indicated response in
53% of the itraconazole recipients and in 46% of the amphotericin B recipients (P = .047, Fleiss test).

Severe adverse events occurred in 19% of the itraconazole group and 34% of
the amphotericin B group (P = .001); 19% and 38% (P = .001), respectively,
withdrew from treatment due to adverse effects. Adverse events considered
related to study therapy occurred in 5% of the itraconazole group and in 54% of
the amphotericin B group (P < .001). Nephrotoxicity (defined as serum
creatinine > 2 times baseline level) occurred in 5% and 24% (P < .001),
respectively; mean creatinine clearance in the treatment groups is shown in
Figure 2
.

Pharmacokinetic evaluation showed that therapeutic plasma itraconazole levels
were achieved in 97% of patients within 3 days of starting treatment. As shown
in Figure 3, mean trough plasma concentrations increased through day 15 and were
somewhat reduced after initiation of oral dosing but remained well over minimum
therapeutic levels.

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