Abstract
Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression.
Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole.
Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour.
Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy.
The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences.
Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects.
Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC) ≥250 μg/L itraconazole, or 750 to 1000 μg/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 μg/L.
The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.
Similar content being viewed by others
References
Joly V, Yeni P. Antifongiques: donnees generates. In: Carbon C, Regnier B, Saimot G, et al. Medicaments anti-infectieux. Paris: Medecine Sciences Flammarion, 1994: 449–53.
Grant SM, Clissold SP. Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989; 37: 310–44.
Odds FC, Vranckx L, Woestenborghs F. Antifungal susceptibility testing of yeasts: evaluation of technical variables for test automation. Antimicrob Agents Chemother 1995; 39: 2051–60.
Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Clin Infect Dis 1997; 24: 235–47.
Hardin TC, Graybill JR, Fetchick R, et al. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother 1988; 32: 1310–3.
Heykants J, Van Peer A, Van de Velde V, et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32 Suppl. 1: 67–87.
Cartledge JD, Midgely J, Gazzard BG. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. J Clin Pathol 1997; 50: 477–80.
Gorlero F, Larosa E, Cauwenbergh G, et al. Itraconazole plasma and vaginal mucosal levels in patients with chronic vaginal candidosis treated with itraconazole 200 mg once daily for 3 consecutive days. Drug Invest 1993; 6: 22–4.
Schafer-Korting M, Korting HC, Lukacs A, et al. Levels of itraconazole in skin blister fluid after a single oral dose during repetitive administration. J Am Acad Dermatol 1990; 22: 211–5.
Barone JA, Koh JG, Bierman RH, et al. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother 1993; 37: 778–84.
Zimmermann T, Yeates RA, Laufen H, et al. Influence of concomitant food intake on oral absorption of two triazole antifungal agents, itraconazole and fluconazole. Eur J Clin Pharmacol 1994; 46: 147–50.
Van de Velde VJ, Van Peer AP, Heykants JJ, et al. Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclo-dextrin formulation of itraconazole. Pharmacotherapy 1996; 16: 424–8.
Jaruratanasirikul S, Kleepkaew A. Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin 1997; 52: 235–7.
Boelaert J, Schurgers M, Matthys E, et al. Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrob Agents Chemother 1988; 32: 1595–7.
Coronel B, Persat F, Dorez D, et al. Itraconazole concentrations during continuous haemofiltration. J Antimicrob Chemother 1994; 34: 448–9.
Arredondo G, Martinez-Jorda R, Calvo R, et al. Protein binding of itraconazole and fluconazole in patients with chronic renal failure. Int J Clin Pharmacol Ther 1994; 32: 361–4.
Smith D, Van de Velde V, Woestenborghs R, et al. The pharmacokinetics of oral itraconazole in AIDS patients. J Pharm Pharmacol 1992; 44: 618–9.
Lazo de la Vega S, Volkow P, Yeates RA, et al. Administration of the antimycotic agents fluconazole and itraconazole to leukaemia patients: a comparative pharmacokinetic study. Drugs Under Exper Clin Res 1994; 20: 69–75.
May DB, Drew RH, Yedinak KC, et al. Effect of simultaneous didanosine administration on itraconazole absorption in healthy volunteers. Pharmacotherapy 1994; 14: 509–13.
Tucker RM, Denning DW, Hanson H, et al. Interaction of azoles with rifampin, phenytoin and carbamazepine: in vitro and clinical observations. Clin Infect Dis 1992; 14: 165–74.
Bonay M, Jonville-Bera AP, Diot P, et al. Possible interaction between phenobarbital, carbamazepine and itraconazole. Drug Saf 1993; 9: 309–11.
Ducharme MP, Slaughter RL, Warbasse LH, et al. Itraconazole and hydroxyitraconazole serum concentrations are reduced more then ten fold by phenytoin. Clin Pharmacol Ther 1995; 58: 617–24.
Partanen J, Jalava KM, Neuvonen PJ. Itraconazole increases serum digoxin concentration. Pharmacol Toxicol 1996; 79: 274–6.
Pohjola Sintonen S, Viitasalo M, Toivonen L, et al. Itraconazole prevents terfenadine metabolism and increase risk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993; 45: 191–3.
McLachlan AJ, Tett SE. Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach. Ther Drug Monit 1998; 20: 390–5.
Buggia I, Zecca M, Alessandrino EP, et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. Anticancer Res 1996; 16 (4A): 2083–8.
Olkkola KT, Backman JT, Neunoven PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481–5.
Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is a potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 56: 601–7.
Kivisto KT, Lamberg TS, Kantola T, et al. Buspirone concentrations are greatly increased by erythromycin and itraconazole. Eur J Clin Pharmacol 1997; 52 Suppl.: A134.
Neuvonen PJ, Jalava KM. Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996; 60: 54–61.
Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther 1997; 61: 410–5.
Stein AG, Daneshmend TK, Warnock DW, et al. The effects of H2-receptor antagonists on the pharmacokinetics of itraconazole, a new oral antifungal [abstract. Br J Clin Pharmacol 1988; 27: 105P–6.
McClean KL, Sheelan GJ. Interaction between itraconazole and digoxin. Clin Infect Dis 1994; 18: 259–60.
Warnock DW, Turner A, Burke J. Comparison of high performance liquid chromatographic and microbiological methods for determination of itraconazole. J Antimicrob Chemother 1988; 21: 93–100.
Hostetler JS, Heykants J, demons KV, et al. Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations. Antimicrob Agents Chemother 1993; 37: 2224–7.
Woestenborghs R, Lorreyne W, Heykants J. Determination of itraconazole in plasma and animal tissues by highperformance liquid chromatography. J Chromatogr 1987; 413: 332–7.
Poirier JM, Lebot M, Descamps P, et al. Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther Drug Monit 1994; 16: 602–7.
Compas D, Touw DJ, de Goede PN. Rapid method for the analysis of itraconazole and hydroxyitraconazole in serum by high-performance liquid chromatography. J Chromatogr Biomed Appl 1996; 687: 453–6.
Poirier JM, Cheymol G. A rapid and specific liquid chromatographic assay for the determination of itraconazole and hydroxyitraconazole in plasma. Ther Drug Monit 1997; 19: 247–8.
Brandsteterova E, Kubalec P, Rady A, et al. Determination of itraconazole and its metabolite using SPE-HPLC. Pharmazie 1995; 50: 597–9.
Lacroix C, Wojciechowski F, Danger P. Simultaneous determination of itraconazole, hydroxy-itraconazole and amphotericin B in human plasma by HPLC with photodiode array detection. Ann Biol Clin 1995; 53: 293–7.
Poirier JM, Hardy S, Isnard F, et al. Plasma itraconazole concentrations in patients with neutropenia: advantages of a divided daily dose regimen. Ther Drug Monit 1997; 19: 525–9.
Berenguer J, Ali NM, Allende MC, et al. Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother 1994; 38: 1303–8.
Boogaerts MA, Verhoef GE, Zachee P, et al. Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma concentrations. Mycoses 1989; 32 Suppl. 1: 103–8.
Tricot G, Joosten E, Boogaerts MA, et al. Ketoconazole vs itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomised studies. Rev Infect Dis 1987; 9 Suppl. 1: S94–99.
Bradford CR, Prentice AG, Warnock DW, et al. Comparison of the multiple dose pharmacokinetics of two formulations of itraconazole during remission induction for acute myeloblastic leukaemia. J Antimicrob Chemother 1991; 28: 555–60.
Persat F, Marzullo C, Guyotat D, et al. Plasma itraconazole concentrations in neutropenic patients after repeated high-dose treatment. Eur J Cancer 1992; 28 (A): 838–41.
Petropoulou T, Liese J, Tintelnot K, et al. Long-term treatment of patients with chronic granulomatous disease (CGD) for prophylaxis against Aspergillus infections [in German. Mycoses 1994; 37 Suppl. 2: 64–9.
Prentice AG, Warnock DW, Johnson SAN, et al. Multiple dose pharmacokinetics of an oral solution of itraconazole in patients receiving chemotherapy for acute myeloid leukaemia. J Antimicrob Chemother 1995; 36: 657–63.
Poirier JM, Berlioz F, Isnard F, et al. Marked intra- and interpatient variability of itraconazole steady state plasma concentrations. Therapie 1996; 51: 163–7.
Levron JC, Le Moing, Chwetzoff E. Exemple of active therapeutic drug monitoring: itraconazole [in French. Therapie 1996; 51: 502–6.
Eichel M, Just-Niibling G, Helm EB, et al. Itraconazole suspension in the treatment of HIV-infected patients suffering from fluconazole-resistant oropharyngeal and oesophageal candidosis [in German. Mycoses 1996; 39 Suppl. 1: 102–6.
Reynes J, Bazin C, Ajana F, et al. Pharmacokinetics of itraconazole (oral solution) in two groups of human immunodeficiency virus-infected adults with oral candidiasis. Antimicrob Agents Chemother 1997; 41: 2554–8.
Haria M, Bryson HM, Goa KL. Itraconazole: a reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 1996; 51: 585–620.
Prentice AG, Warnock DW, Johnson SAN, et al. Multiple dose pharmacokinetics of an oral solution of itraconazole in autologous bone marrow transplant recipients. J Antimicrob Chemother 1994; 34: 247–52.
Vandewoude K, Vogelaers D, Decruyenaere J, et al. Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units. Antimicrob Agents Chemother 1997; 41: 2714–8.
Graybill JR. Is there a correlation between serum antifungal drug concentration and clinical outcome? J Infect 1994; 28 Suppl. 1: 17–24.
British Society for Antimicrobial Chemotherapy Working Party. Laboratory monitoring of antifungal chemotherapy. Lancet 1991; 337: 1577–80.
Working Party of the British Society for Antimicrobial Chemotherapy. Chemoprophylaxis for candidosis and aspergillosis in neutropenia and transplantation: a review and recommendations. J Antimicrob Chemother 1993; 32: 5–21.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Poirier, JM., Cheymol, G. Optimisation of Itraconazole Therapy Using Target Drug Concentrations. Clin Pharmacokinet 35, 461–473 (1998). https://doi.org/10.2165/00003088-199835060-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199835060-00004