Summary
The range of oral antifungal therapy has been expanded recently by the introduction of itraconazole, fluconazole and terbinaflne. These agents have a broader spectrum of activity than griseofulvin and flucytosine, and induce less liver toxicity than ketoconazole. Treatment with these agents may be optimised by application of pharmacokinetic principles.
Griseofulvin, ketoconazole and itraconazole should be administered with food to ensure adequate absorption. Maximal absorption of griseofulvin is achieved by administration of the drug as a solid solution in polyethylene glycol. Absorption of azole antifungal agents is impaired by high gastric pH, which is observed in some patients with acquired immunodeficiency syndrome. It is also impaired by frequent vomiting, which commonly occurs in patients with neutropenia. Furthermore, antacids, H2-antagonists and sucralfate interfere with absorption of ketoconazole.
The newer oral antifungals are more slowly eliminated and associated with less pronounced drug interactions than ketoconazole. As with ketoconazole, itraconazole and fluconazole influence cyclosporin metabolism. These effects are of clinical relevance and necessitate cyclosporin dosage reduction. However, the cyclosporin dosage reduction required during coadministration of itraconazole and fluconazole (50 to 55%) is less than that required when ketoconazole is concomitantly administered (85%). Monitoring of cyclosporin concentrations during coadministration with these agents is necessary to avoid nephrotoxicity. Drug monitoring is also advisable when phenytoin, carbamazepine or rifampicin (rifampin) are administered concomitantly with azoles, due to a mutual influence on drug metabolism.
The antifungal activity of itraconazole is not related exclusively to free drug concentrations. Therefore, the low protein binding of fluconazole does not place this agent at an advantage over itraconazole in the treatment of fungal meningitis. However, terbinafine may be superior to itraconazole for the treatment of tinea unguium, another recalcitrant fungal disease, because terbinafine more rapidly penetrates the nail plate. During repeated use, itraconazole concentrations increase slowly in the nail plate. Steady-state concentrations are reached in the stratum corneum only after several weeks’ administration. Following cessation of treatment, terbinafine, itraconazole and ketoconazole concentrations in keratinised tissues decline slowly. This allows a short duration of drug treatment.
Some clinical trials suggest that low concentrations of flucytosine, griseofulvin and itraconazole are associated with treatment failure. Flucytosine-induced myelotoxicity also appears to be concentration dependent. This adverse reaction may be caused by fluorouracil (which is produced by metabolism of flucytosine by enterobacillary flora in the gut) rather than by the parent compound.
Similar content being viewed by others
References
Back DJ, Stevenson P, Tjia JF. Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinylestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro. British Journal of Clinical Pharmacology 28: 166–170, 1989
Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. Journal of Pediatrics 116: 791–797, 1990
Balfour JA, Faulds D. Terbinafine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 43: 259–284, 1992
Blum RA, D’Andrea DT, Florentino BM, Wilton JH, Hilligoss DM, et al. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Annals of Internal Medicine 114: 755–757, 1991a
Blum RA, Wilton JH, Hilligoss DM, Gardner MJ, Henry EB, et al. Effect of fluconazole on the disposition of phenytoin. Clinical Pharmacology and Therapeutics 49: 420–425, 1991b
Boelaert J, Schurgers M, Matthys E, Daneels R, Van Peer A, et al. Itraconazole pharmacokinetics in patients with renal dysfunction. Antimicrobial Agents and Chemotherapy 32: 1595–1597, 1988
Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Reviews of Infectious Diseases 12 (Suppl. 3): S318–S326, 1990
Brammer KW, Feczko JM. Single-dose oral fluconazole in the treatment of vaginal candidosis. Annals of the New York Academy of Sciences 554: 561–563, 1988
Brasseur P, Bonmarchand G, Caron F, Lecomte F, Leroy J, et al. Diffusion de la 5-fluorocytosine dans les sécrétions bronchiques chez l’insuffisant respiratoire. Annales de Biologie Clinique 45: 685–688, 1987
Canafax DM, Graves NM, Hilligoss DM, Carleton BC, Gardner MJ, et al. Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 51: 1014–1018, 1991
Cauwenbergh G. Itraconazole: the first orally active antifungal for single-day treatment of vaginal candidosis. Current Therapeutic Research 41: 210–214, 1987
Cauwenbergh G, Degreef H, Heykants J, Woestenborghs R, Van Rooy P, et al. Pharmacokinetic profile of orally administered itraconazole in human skin. Journal of the American Academy of Dermatology 18: 263–268, 1988
Chin T, Fong IW, Vandenbroucke A. Pharmacokinetics of fluconazole in serum and cerebrospinal fluid in a patient with AIDS and cryptococcal meningitis. Pharmacotherapy 10: 305–307, 1990
Daneshmend TK. Diseases and drugs but not food decrease ketoconazole bioavailability. British Journal of Clinical Pharmacology 29: 783–784, 1990
Daneshmend TK, Warnock DW. Clinical pharmacokinetics of systemic antifungal drugs. Clinical Pharmacokinetics 8: 17–42, 1983
Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clinical Pharmacokinetics 14: 13–34, 1988
De Beule K, Lubin G, Cauwenbergh G. Safety aspects of itraconazole therapy in vaginal candidosis, dermatomycosis, and onychomycosis: a review. Current Therapeutic Research 49: 814–822, 1991
Debruyne D, Ryckelynck J-P, Moulin M, Hurault de Ligny B, Levaltier B, et al. Pharmacokinetics of fluconazole in patients undergoing continuous ambulatory peritoneal dialysis. Clinical Pharmacokinetics 18: 491–498, 1990
Denning DW, Tucker RM, Hanson LH, Stevens DA. Itraconazole in opportunistic mycoses: cryptococcosis and aspergillosis. Journal of the American Academy of Dermatology 23: 602–607, 1990
Drouhet E. Antifungal agents. Antibiotics and Chemotherapy 25: 253–288, 1978
Epstein WL, Shah VP, Riegelman S. Griseofulvin levels in stratum corneum. Archives of Dermatology 106: 344–348, 1972
Faergemann J, Laufen H. Levels of fluconazole in serum, stratum corneum, epidermis-dermis (without stratum corneum) and eccrine sweat. Clinical and Experimental Dermatology 18: 102–106, 1993
Faergemann J, Zehender H, Jones T, Maibach HI. Terbinafine levels in serum, stratum corneum, dermis-epidermis (without stratum corneum), hair, sebum and eccrine sweat. Acta Dermato-Venereologica 71: 322–326, 1991
Finlay AY, Lever L, Thomas R, Dykes PJ. Nail matrix kinetics of oral terbinafine in onychomycosis and normal nails. Journal of Dermatological Treatment 1 (Suppl. 2): 51–53, 1990
First MR, Schroeder TJ, Alexander JW, Stephens GW, Weiskittel P, et al. Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients. Transplantation 51: 365–370, 1991
Ginsburg CM, McCracken Jr GH, Petruska M, Olsen K. Effect of feeding on bioavailability of griseofulvin in children. Journal of Pediatrics 102: 309–311, 1983
Grant SM, Clissold SP. Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37: 310–344, 1989
Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 39: 877–916, 1990
Graybill JR. Chemotherapy of systemic mycoses. Seminars in Respiratory Medicine 9: 207–216, 1987
Hägermark Ö, Berlin A, Wallin I, Boréus LO. Plasma concentrations of griseofulvin in healthy volunteers and out-patients treated for onychomycosis. Acta Dermato-Venereologica 56: 289–296, 1976
Haneke E. Verweildauer von Ketoconazol in der Haut nach oraler Behandlung. Hautarzt 38: 93–96, 1987
Haneke E. Fluconazole levels in human epidermis and blister fluid. British Journal of Dermatology 123: 273–277, 1990
Harris R, Jones HE, Artis WM. Orally administered ketoconazole: route of delivery to the human stratum corneum. Antimicrobial Agents and Chemotherapy 24: 876–882, 1983
Harris BE, Manning BW, Federle TW, Diasio RB. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrobial Agents and Chemotherapy 29: 44–48, 1986
Hay KD. Candidosis of the oral cavity: recognition and management. Drugs 36: 633–642, 1988
Hay RJ. Pharmacokinetic evaluation of fluconazole in skin and nails. International Journal of Dermatology 31 (Suppl. 2): 6–7, 1992
Heel RC, Brogden RN, Carmine A, Morley PA, Speight TM, et al. Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 23: 1–36, 1982
Heykants J, Michiels M, Meuldermans W, Monbaliu J, Lavrijsen K, et al. The pharmacokinetics of itraconazole in animals and man: an overview. In Fromtling (Ed.) Recent trends in the discovery, development and evaluation of antifungal agents, pp. 223–249, Prous Science Publishers, Barcelona, 1987
Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 32 (Suppl. 1): 67–87, 1989
Houang ET, Chappatte O, Byrne D, MacRae PV, Thorpe JE. Fluconazole levels in plasma and vaginal secretions of patients after a 150-milligram single oral dose and rate of eradication of infection in vaginal candidiasis. Antimicrobial Agents and Chemotherapy 34: 909–910, 1990
Humphrey MJ, Jevons S, Tarbit MH. Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans. Antimicrobial Agents and Chemotherapy 28: 648–653, 1985
Ittel TH, Legier UF, Polak A, Glöckner WM, Sieberth HG. 5-Fluorocytosine kinetics in patients with acute renal failure undergoing continuous hemofiltration. Chemotherapy 33: 77–84, 1987
Jensen JC. Clinical pharmacokinetics of terbinafine (Lamisil). Clinical and Experimental Dermatology 14: 110–113, 1989
Jensen JC. Pharmacokinetics of Lamisil® in humans. Journal of Dermatological Treatment 1 (Suppl. 2): 15–18, 1990
Korting HC, Schäfer-Korting M. Is tinea unguium still widely incurable? a review three decades after griseofulvin. Archives of Dermatology 128: 243–248, 1992
Korting HC, Lukacs A, Schäfer-Korting M. Skin blister fluid levels of ketoconazole during repetitive administration in man. Mycoses 32: 39–45, 1989
Kowalsky SF. Drug interactions with fluconazole. Pharmacotherapy 10 (Suppl.): 170S–173S, 1990
Kramer MR, Marshall SE, Denning DW, Keogh AM, Tucker RM, et al. Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Annals of Internal Medicine 113: 327–329, 1990
Lachapelle JM, De Doncker P, Tennstedt D, Cauwenbergh G, Janssen PAJ. Itraconazole compared with griseofulvin in the treatment of tinea corporis/cruris and tinea pedis/manus: an interpretation of clinical results of all completed double-blind studies with respect to the pharmacokinetic profile. Dermatology 184: 45–50, 1992
Lake-Bakaar G, Tom W, Lake-Bakaar D, Gupta N, Beidas S, et al. Gastropathy and ketoconazole malabsorption in the acquired immuno-deficiency syndrome (AIDS). Annals of Internal Medicine 109: 471–473, 1988
Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole in the United Kingdom. British Medical Journal 294: 419–420, 1987
Lazar JD, Wilner KD. Drug interactions with fluconazole. Reviews of Infectious Diseases 12 (Suppl. 3): S327–S333, 1990
Lever LR, Dykes PJ, Thomas R, Finlay AY. How orally administered terbinafine reaches the stratum corneum. Journal of Dermatological Treatment 1 (Suppl. 2): 23–25, 1990
Lin C, Lim J, DiGiore C, Gural R, Symchowicz S. Comparative bioavailability of a microsize and ultramicrosize griseofulvin formulation in man. Journal of International Medical Research 20: 274–277, 1982
Lin C, Symchowicz S. Absorption, distribution, metabolism, and excretion of griseofulvin in man and animals. Drug Metabolism Reviews 41: 75–95, 1975
Machard B, Misslin P, Lemaire M. Influence of plasma protein binding on the brain uptake of an antifungal agent, terbinafine, in rats. Journal of Pharmacy and Pharmacology 41: 700–704, 1989
Malet-Martino MC, Martino M, de Forni M, Andremont A, Hartmann O, et al. Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora status exist? A report of two cases using fluorine-19 magnetic resonance spectroscopy. Infection 19: 178–180, 1991
Matthieu L, De Doncker P, Cauwenbergh G, Woestenborghs R, Van de Velde V, et al. Itraconazole penetrates the nail via the nail matrix and the nail bed — an investigation in onychomycosis. Clinical and Experimental Dermatology 16: 374–376, 1991
McNulty RM, Lazor JA, Sketch M. Transient increase in plasma quinidine concentrations during ketoconazole-quinidine therapy. Clinical Pharmacy 8: 222–225, 1989
Milliken S, Helenglass G, Powles R. Fluconazole pharmacokinetics following oral dosage in leukaemic patients receiving autologous bone marrow transplantation. Bone Marrow Transplantation 3: 324–325, 1988
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, et al. Torsades des pointes occurring in association with terfenadine use. Journal of the American Medical Association 264: 2788–2790, 1990
Perfect JR, Durack DT. Penetration of imidazoles and triazoles into cerebrospinal fluid of rabbits. Journal of Antimicrobial Chemotherapy 16: 81–86, 1985
Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrobial Agents and Chemotherapy 29: 579–583, 1986
Piérard GE, Rurangirwa A, Piérard-Franchimont C. Bioavailability of fluconazole and ketoconazole in human stratum corneum and oral mucosa. Clinical and Experimental Dermatology 16: 168–171, 1991
Piscitelli SC, Goss TF, Wilton JH, D’Andrea DT, Goldstein H, et al. Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrobial Agents and Chemotherapy 35: 1765–1771, 1991
Polak A. Pharmacokinetics of amphotericin B and flucytosine. Postgraduate Medical Journal 55: 667–670, 1979
Ritter W. Pharmacokinetics of azole compounds. In Berg & Plempel (Eds) Sterol biosynthesis inhibitors, pp. 397–429, Ellis Horwood, Chichester, 1988
Schäfer-Korting M, Korting HC, Amann F, Peuser R, Lukacs A. Influence of albumin on itraconazole and ketoconazole antifungal activity: results of a dynamic in vitro study. Antimicrobial Agents and Chemotherapy 35: 2053–2056, 1991
Schäfer-Korting M, Korting HC, Dorn M, Mutschier E. Ketoconazole concentrations in human skin blister fluid and plasma. International Journal of Clinical Pharmacology, Therapy and Toxicology 22: 371–374, 1984
Schäfer-Korting M, Korting HC, Lukacs A, Heykants J, Behrendt H. Levels of itraconazole in skin blister fluid after a single oral dose and during repetitive administration. Journal of the American Academy of Dermatology 22: 211–215, 1990
Schäfer-Korting M, Korting HC, Mutschier E. Human plasma and skin blister fluid levels of griseofulvin following a single oral dose. European Journal of Clinical Pharmacology 29: 109–113, 1985a
Schäfer-Korting M, Korting HC, Mutschier E. Human plasma and skin blister fluid levels of griseofulvin after its repeated administration. European Journal of Clinical Pharmacology 29: 351–354, 1985b
Schuster I, Schaude M, Schatz F, Mieth H. Preclinical aspects of allylamines. In Berg & Plempel (Eds) Sterol biosynthesis inhibitors, pp. 449–470, Ellis Horwood, Chichester, 1988
Shiba K, Saito A, Miyahara T. Safety and pharmacokinetics of single oral and intravenous doses of fluconazole in healthy subjects. Clinical Therapeutics 12: 206–215, 1990
Sobel JD. Individualizing treatment of vaginal candidiasis. Journal of the American Academy of Dermatology 23: 572–576, 1990
Stein AG, Daneshmend TK, Warnock DW, Bhaskar N, Burke J, et al. The effects of H2-receptor antagonists on the pharmacokinetics of itraconazole, a new oral antifungal. British Journal of Clinical Pharmacology 27: 105P–106P, 1989
Terhaag B, Pachaly C, Frank G, Le Petit G, Feller K. Zur Entwicklung des Steady-state-Plasma-Spiegels von Griseofulvin nach wiederholter Gabe beim Menschen. Zeitschrift für Klinische Medizin 41: 1371–1374, 1986
Torregrosa V, De la Torre M, Campistol JM, Oppenheimer F, Ricart MJ, et al. Interaction of fluconazole with cyclosporine A. Nephron 60: 125–126, 1992
Tricot G, Joosten E, Boogaerts MA, Vande Pitte J, Cauwenbergh G. Ketoconazole vs itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomized studies. Reviews of Infectious Diseases 9 (Suppl. 1): S94–S99, 1987
Tucker RM, Denninng DW, Hanson LH, Rinaldi MG, Graybill JR, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clinics in Infectious Diseases 14: 165–174, 1992
Tucker RM, Williams PL, Arathoon EG, Levine BE, Hartstein AI, et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrobial Agents and Chemotherapy 32: 369–373, 1988
Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Cauwenbergh G. The effect of food and dose on the oral systemic availability of itraconazole in healthy subjects. European Journal of Clinical Pharmacology 36: 423–426, 1989
Van’t Wout JW, de Graeff-Meeder ER, Paul LC, Kuis W, Van Furth R. Treatment of two cases of cryptococcal meningitis with fluconazole. Scandinavian Journal of Infectious Disease 20: 193–198, 1988
Vialaneix JP, Malet-Martino MC, Hoffmann JS, Pris J, Martino R. Direct detection of new flucytosine metabolites in human biofluids by 19F nuclear magnetic resonance. Drug Metabolism and Disposition 15: 718–724, 1987
Wells C, Lever AML. Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge. Journal of Infection 24: 111–112, 1992
Willemsen M, De Doncker P, Willems J, Woestenborghs R, Van de Velde V, et al. Post-treatment itraconazole levels in the nail: new implications for treatment of onychomycosis. Journal of the American Academy of Dermatology 26: 731–735, 1992
Yamashita SK, Ludwig EA, Middleton Jr E, Jusko WJ. Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone. Clinical Pharmacology and Therapeutics 49: 558–570, 1991
Zürcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of prednisolone. Clinical Pharmacology and Therapeutics 45: 366–372, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schäfer-Korting, M. Pharmacokinetic Optimisation of Oral Antifungal Therapy. Clin. Pharmacokinet. 25, 329–341 (1993). https://doi.org/10.2165/00003088-199325040-00006
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199325040-00006