Pharmacokinetics of itraconazole following oral administration to normal volunteers

Hardin, Thomas C.; Graybill, John R.; Fetchick, Richard J.; Woestenborghs, Robert; Rinaldi, Michael G.; Kuhn, John G.

doi:10.1128/aac.32.9.1310

Cited by 268 publications

(170 citation statements)

References 6 publications

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“…The higher (600-mg) dose of itraconazole gave serum values above those previously reported for a dose of 400 mg/day (12). In studies with a dose of 400 mg/day, a dose and time dependency of the half-life was noted, with a markedly increased half-life at higher doses and after 2 weeks of treatment (12). The long half-life (>24 h) and resultant drug accumulation over 2 weeks may have accounted for the delayed onset of adrenal insufficiency in the patient.…”

Section: Discussionsupporting

confidence: 61%

High-dose itraconazole in the treatment of severe mycoses

Sharkey

Rinaldi

Dunn

et al. 1991

Antimicrob Agents Chemother

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138

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Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (<2.5 ,ug/ml) in both patients. All other patients had mean trough levels in serum above 5 ,ug/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

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Section: Discussionsupporting

confidence: 61%

High-dose itraconazole in the treatment of severe mycoses

Sharkey

Rinaldi

Dunn

et al. 1991

Antimicrob Agents Chemother

Self Cite

138

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“…Important variations in plasma itraconazole concentrations observed in patients, compared with healthy volunteers, 3 are related to individual conditions of drug absorption, thereby justifying plasma measurements. A plasma concentration of unchanged itraconazole (ITRA) у250 ng/ml is considered necessary to obtain a therapeutic effect on Aspergillus.…”

mentioning

confidence: 99%

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Michallet

Persat

Kranzhöfer

et al. 1998

Bone Marrow Transplant

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Summary:A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (C min ) and 4 h later (C max ) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of C min ITRA and OH-ITRA, respectively, were 287 ؎ 109 ng/ml and 629 ؎ 227 ng/ml at day ؊1 and 378 ؎ 147 ng/ml and 725 ؎ 242 ng/ml at day +1. The maximum C min values were observed at day +3. Six patients at day ؊1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases. Keywords: pharmacokinetics; itraconazole solution; BMT; TBI Prophylaxis and treatment of systemic fungal infections in patients undergoing allogeneic bone marrow transplant (BMT) remain important issues. Broad spectrum antifungals with a low toxicity and good bioavailability are being sought. Ideally, orally administered medications given to prevent invasive aspergillosis should provide a systemic effect. However several factors are likely to impair bioavailability of orally administered medications in allogeneic BMT patients: nausea and vomiting mainly during conditioning regimen period, mucositis during aplasia and acute graft-versus-host disease (GVHD) later.Itraconazole, a triazole broad spectrum antifungal 1,2 is presently marketed as capsules. Important variations in plasma itraconazole concentrations observed in patients, compared with healthy volunteers, 3 are related to individual conditions of drug absorption, thereby justifying plasma measurements. A plasma concentration of unchanged itraconazole (ITRA) у250 ng/ml is considered necessary to obtain a therapeutic effect on Aspergillus. 4 However, since hydroxy-itraconazole (OH-ITRA) has a similar antifungal effect to unchanged ITRA, 5 the active fraction is represented by the sum of unchanged ITRA and its active metabolite OH-ITRA with an effective total level of about 1000 ng equivalents/ml. This effective level could be estimated from the effective plasma levels of unchanged ITRA (Ϸ250 ng/ml) 4,6 and metabolic ratio in human plasma between ITRA and OH-ITRA ([OH-ITRA]/[ITRA] Ϸ2). 7 However the capsule formulation is of limited use in allogeneic BMT: its bioavailability is reduced when administered under fasting conditions and when coadministered with antacids. 8 Itraconazole oral solution is a new formulation where ITRA is solub...

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“…25 Variation in the maximum concentration (C max ) of itraconazole among our volunteers is comparable to those reported by others. 7,25,26 The e¡ect of eating on itraconazole pharmacokinetics was also previously documented. 27 The potent inhibitory activity of itraconazole for the CYP3A4 subfamily has been well recognized in clinical therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…6 In addition, a signi¢cant variation in pro¢les of itraconazole concentration in plasma versus time have been reported. 7 A reliable method for monitoring plasma concentrations of itraconazole is therefore needed for optimizing therapy and avoiding adverse e¡ects of drug interaction. Several high-performance liquid chromatographic (HPLC) methods have been reported for the determination of itraconazole concentrations.…”

Section: Introductionmentioning

confidence: 99%