- Email: [email protected]
Itraconazole
Therapeutic Review
Itraconazole Krista A. Keller, DVM
I
traconazole is a synthetic triazole used in both human and veterinary medicine. This antifungal agent works by altering the cellular membranes of fungi, increasing membrane permeability, and allowing cellular content leakage and impaired uptake of pertinent extracellular components.1 Itraconazole has additionally been shown to be an antiangiogenic agent; it inhibits endothelial cell cycle progression at the G1 phase and has been shown to block vascular endothelial growth factor– dependent angiogenesis in vivo. The true potential of the antiangiogenic nature of this drug has not been fully evaluated at this time.2 Several commercially available preparations of itraconazole are marketed in the United States, including itraconazole oral suspension (Sporanox, 10 mg/mL; Janssen Pharmaceuticals, Titusville, NJ USA), itraconazole capsules (Sporanox, 100 mg; Janssen Pharmaceuticals), and injectable itraconazole (Sporanox, 10 mg/ mL; Janssen Pharmaceuticals). Both the oral suspension and the injectable form contain cyclodextrin. Cyclodextrin, or hydroxypropyl-beta-cyclodextrin, is a ring of substituted glucose molecules. The use of cyclodextrin increases the absorption, and thus, the bioavailability of itraconazole.3 After administration of oral itraconazole-cyclodextrin formulations, absorption of cyclodextrin is negligible and the compound is broken down by gastrointestinal microflora to glucose molecules that are then absorbed.3 When itraconazole is administered in the injectable form, cyclodextrin is rapidly cleared by glomerular filtration with little accumulation in the body.3 When taken orally, itraconazole absorption is highly dependent on gastric pH and the formulation used.3-8 Itraconazole suspension, with cyclodextrin, given under fasted conditions has a more rapid absorption and higher bioavailability when compared with patients that have not been fasted.4,8,9 In contrast, itraconazole capsules show higher plasma concentrations when administered at mealtimes.8 This trend for better absorption and higher tissue concentrations with the capsule formulations being administered with food has been confirmed in pi-
156
geons.10 Because of the dependence of itraconazole capsules on low gastric pH, concurrent use of antacids11 and proton pump inhibitors12 are not recommended when using itraconazole. In animal species treated by veterinarians, several studies have evaluated the effect of different formulations of itraconazole on bioavailability and absorption. In penguins, it was found that commercially available itraconazole suspension had superior absorption to compounded itraconazole suspensions that lack cyclodextrin.5 A second study in penguins showed that commercially available capsules were absorbed better than bulk itraconazole powder.6 In a study comparing the pharmacokinetic profiles of 2 commercially available itraconazole formulations in horses (Equus ferus), it was found that administration of the oral suspension resulted in more consistent absorption and higher maximum concentrations when compared with horses administered the capsule formulation.7 On absorption, itraconazole is highly protein bound to blood cells and plasma proteins. Only 0.2% of the drug is found unbound in humans3 and 1.2% in horses.7 Itraconazole is widely distributed to tissues, reaching highest levels in lipophilic tissues such as the skin, sebum, and the female reproductive tract.1,3 Itraconazole is also found in high concentrations in the nails and skin where the drug is incorporated into the matrix of the nail.3 Minimal concentrations of this drug are found in the noninflamed tissues of the aqueous humor of the eye, cerebrospinal fluid, urine, and saliva.1,3,7 From the Department of Clinical Sciences, Louisiana State University, School of Veterinary Medicine, Baton Rouge, LA USA Address correspondence to: Krista A. Keller, DVM, Department of Clinical Sciences, Louisiana State University, School of Veterinary Medicine, Skip Bertman Dr, Baton Rouge, LA 70803. E-mail: [email protected]. © 2011 Elsevier Inc. All rights reserved. 1557-5063/11/2002-$30.00 doi:10.1053/j.jepm.2011.02.012
Journal of Exotic Pet Medicine, Vol 20, No 2 (April), 2011: pp 156 –160
Therapeutic Review
The liver metabolizes itraconazole into several different metabolites, including the active hydroxyitraconazole.1,3 There is significant variation in the metabolism pattern, indicated by the itraconazole: hydroxyitraconazole ratio, in animal species treated by veterinarians. For example, horses have been found to have no measureable levels of plasma hydroxyitraconazole after itraconazole administration,7 whereas pigeons (Columba livia) have been found to have hydroxyitraconazole concentrations higher than itraconazole in tissues.10 The half-life of itraconazole in humans has been reported to be between 21 and 64 hours, and because of its long half-life, steady-state plasma concentrations may not be reached for 6 days in humans,1,3 up to 14 days in red-tailed hawks (Buteo jamaicensis),13 and 21 days in cats (Felis catus).14 Most itraconazole metabolites are excreted through the bile and urine. Unmetabolized itraconazole is not detected in the urine, but 3% to 18% of the dose is detected in the feces.3 Itraconazole and its metabolites have been shown to be cytochrome P450 and P-glycoprotein inhibitors.15,16 Because itraconazole and its metabolites are cytochrome P450 and P-glycoprotein inhibitors, therapy with other medications metabolized by this route must be monitored for signs of toxicity. Specific medications include digoxin,3,17 tacrolimus,18 cyclophosphamide,19 dexamethasone,20 diazepam,21 and oxycodone.22 In some cases, itraconazole is given to therapeutically increase serum levels of medications to reduce the cost of expensive drugs (e.g., cyclosporine).23 Rifampin, when used concurrently with itraconazole, has been shown to decrease therapeutic concentrations of itraconazole in both humans3,24 and animals.25 Fungal disease is the main indication for using itraconazole for therapeutic purposes. Aspergillus spp. represents the underlying etiology of a large percentage of fungal disease cases diagnosed in veterinary medicine. Animals that have been treated successfully for Aspergillus using itraconazole include the guinea pig (Cavia porcellus),26 horses,27-29 and cats.30 Additionally, itraconazole should be considered as a primary drug of choice for the treatment of aspergillosis in birds31,32 and is the treatment of choice for prophylaxis and treatment of aspergillosis in penguins.5 In a recent study, invasive mold infections in immunocompromised and immunosuppressed human patients represented a significant burden on human health care, with 2.36 cases occurring in every 100,000 inhabitants.33 Of those human cases, 67% were from Aspergillus spp.33 Some of what we know regarding the use of itraconazole in nondomestic
157 species was generated from experimental models of invasive pulmonary aspergillosis for humans using laboratory animals. Mice (Mus musculus) and rabbits (Oryctolagus cuniculus) with experimentally induced invasive aspergillosis were found to respond to itraconazole therapy.34,35 Although itraconazole has been an important antifungal in human medicine, the advent of newer azole antifungals has decreased human medicine’s dependence on it, with less than 1% of recently studied patients receiving this therapy alone.33 Despite the heavy reliance of veterinary medicine on itraconazole, several strains of Aspergillus spp. have shown acquired resistance to this drug.36 Itraconazole has been used to manage fungal diseases (other than aspergillosis) in a variety of different domestic and exotic pet mammals. It has been used to successfully eliminate dermatophytosis in guinea pigs,37 ferrets (Mustelus putorious furo),38 dogs (Canis familiaris), and cats39; cryptococcosis in hamsters (Mesocricetus auratus)40 and ferrets41,42; histoplasmosis in ferrets38; blastomycosis in ferrets38; and coccidiodomycosis in rabbits43 and horses.44 Additionally, itraconazole has been used to successfully treat fungal rhinitis,45 fungal osteomyelitis caused by Cladosporium spp.,46 fungal pneumonia,47 and systemic fungal disease by Colletotrichum spp.48 In nonmammalian species, fungal blepharitis and dermatitis were successfully treated in a Eurasian eagle owl (Bubo bubo hispanus) and a Peregrine falcon hybrid (Falco peregrinus ⫻ F. rusticolus).49,50 In reptiles and amphibians, itraconazole has been shown to effectively treat fungal epidemics, including infections with chytrid fungus in amphibians51,52 and Chrysosporium anamorph of Nannizziopsis vriesii in reptiles.53,54 Lastly, itraconazole has been administered to horseshoe crabs (Limulus polyphemus) with an unspeciated fungal disease.55 The most common adverse side effects associated with itraconazole administration in humans are abdominal pain, nausea, vomiting, and dyspepsia.56 In one study, 2/3 of human patients receiving oral itraconazole suffered from a gastrointestinal disorder.57 Liver enzyme concentrations should be monitored during treatment because of potential hepatotoxicity.56 Rarely, cholestasis with accompanying hyperbilirubinemia has been found in humans treated with itraconazole.58 More recently, itraconazole pulse therapy has been evaluated as a way to decrease some of the negative side effects described with itraconazole without sacrificing plasma concentrations and efficacy.59 In veterinary medicine, as with humans, gastrointestinal signs have been noted during itraconazole
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therapy. Raptors are described to have significant anorexia when placed on itraconazole therapy.60 Additionally, bearded dragons (Pogona vitticeps) administered itraconazole at the high end of the dosing range showed significant anorexia and weight loss.61 Hepatotoxicity appears to be more rare in animals treated by veterinarians, but has been described in 2 cats.30,45 Several pharmacokinetics studies have been reported in birds.13,62,63 In blue-fronted Amazon parrots (Amazona aestiva aestiva), the subject birds were gavaged the contents of the commercially available capsules mixed with 0.1 N hydrochloric acid and diluted with orange juice. The study showed that a dose of 5 mg/kg every 24 hours achieved adequate plasma concentrations to be inhibitory to most Aspergillus spp.62 In a pigeon study, the birds were given capsules under fasting conditions. The study showed a dose of 6 mg/kg every 12 hours reached adequate plasma concentrations for treatment of susceptible fungal infections in most tissues outside of the lungs. To reach adequate fungicidal concentrations in the lungs, a dosing regimen of 26 mg/kg every 12 hours was recommended.63 A study in red-tailed hawks found that providing the oral itraconazole suspension at 10 mg/kg every 24 hours was sufficient for treating aspergillosis.13 Captive Humboldt penguins (Spheniscus humboldti) should be dosed at 8.5 mg/kg orally twice per day or 20 mg/kg orally once a day using commercially available capsules to achieve acceptable steady-state therapeutic levels.6 Although a dosing interval was not provided for black-footed penguins (Spheniscus demersus), 7 mg/kg orally of the commercially available itraconazole suspension resulted in adequate therapeutic concentrations.5 The differences noted in the pharmacokinetic studies described above provide scientific evidence that itraconazole doses vary for different animal species and when different formulations of the drug are administered. Consequently, care should be taken when trying to determine a proper dose of itraconazole for a particular patient so that one has the best chance of successfully treating the fungal disease.
4.
5.
6.
7.
8.
9.
10. 11. 12. 13. 14.
15.
16.
17. 18.
References 1. 2. 3.
Plumb DV: Itraconazole, in Plumb DV (ed): Veterinary Drug Handbook (ed 5), Ames, IA, Blackwell Publishing, pp 431-433, 2005 Chong CR, Xu J, Lu J, et al: Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol 2:263-270, 2007 Willems L, van der Geest R, de Beule K: Itraconazole oral solution and intravenous formulations: a review
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of pharmacokinetics and pharmacodynamics. J Clin Pharm Ther 26:159-169, 2001 Van de Velde VJ, Van Peer AP, Heykants JJ, et al: Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole. Pharmacotherapy 16:424-428, 1996 Smith JA, Papich MG, Russell G, et al: Effects of compounding on pharmacokinetics of itraconazole in black-footed penguins (Spheniscus demersus). J Zoo Wildl Med 41:487-495, 2010 Bunting EM, Madi NA, Cox S, et al: Evaluation of oral itraconazole administration in captive Humboldt penguins (Spheniscus humboldti). J Zoo Wildl Med 40:508-518, 2009 Davis JL, Salmon JH, Papich MG: Pharmacokinetics and tissue distribution of itraconazole after oral and intravenous administration to horses. Am J Vet Res 66:1694-1701, 2005 Van Peer A, Woestenborghs R, Heykants J, et al: The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 36:423-426, 1989 Barone JA, Mospovitz BL, Guarnieri J, et al: Food interaction and steady state pharmacokinetics of itraconazole oral solution in healthy volunteers. Pharmacotherapy 18:295-301, 1998 Orosz SE, Schroeder EC, Cox SK, et al: The effects of formulation on the systemic availability of itraconazole in pigeons. J Avian Med Surg 9:255-262, 1995 Lohitnavy M, lohitnavy O, Thangkeattiyanon O, et al: Reduced oral itraconazole bioavailability by antacid suspension. J Clin Pharm Ther 30:201-206, 2005 Jaruratanasirikul S, Sriwiriyajan S: Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 54:159-161, 1998 Jones MP, Orosz SE, Cox SK, et al: Pharmacokinetic disposition of itraconazole in red-tailed hawks (Buteo jamaicensis). J Avian Med Surg 14:15-22, 2000 Boothe DM, Herring I, Calvin J, et al: Itraconazole disposition after single oral and intravenous and multiple oral dosing in healthy cats. Am J Vet Res 58:872-877, 1997 Templeton I, Peng C-C, Thummel KE, et al: Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data. Clin Pharmacol Ther 88:499-505, 2010 Nivoix Y, Leveque D, Herbrecht R, et al: The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet 47(12):779792, 2008 Jalava KM, Partanen J, Neuvonen PJ: Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 19:609-613, 1997 Leather H, Boyette Rm, Tian L, et al: Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporine A in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 12:325-334, 2006 Marr KA, Leisenring W, Crippa F, et al: Cyclophosphamide metabolism is affected by axole antifungals. Blood 103:1557-1559, 2004 Varis R, Kivisto KT, Backman JT, et al: The cytochrome P4503A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone
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and enhances its adrenal-suppresant effect. Clin Pharmacol Ther 68:487-494, 2000 Ahonen J, Olkkola KT, Neuvonen PJ: The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam. Fundam Clin Pharmacol 10:314-318, 1996 Saari TI, Gronlund J, Hagelberg NM, et al: Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 66:387-397, 2010 Katayama M, Katayama R, Kamishina H: Short communication: effects of multiple oral dosing of itraconazole on the pharmacokinetics of cyclosporine in cats. J Feline Med Surg 12:512-514, 2010 Drayton J, Dickinson G, Rinaldi MG: Co-administration of rifampin and itrazonazole leads to undetectable levels of serum itraconazole. Clin Infect Dis 18:266, 1994 Kaltanbach G, Leveqe D, Peter JD, et al: Pharmacokinetic interaction between itraconazole and rifampin in Yucatan miniature pigs. Antimicrob Agents Chemother 40:2043-2046, 1996 Marshall KL: Fungal diseases in small mammals: therapeutic trends and zoonotic considerations. Vet Clin Exotic Anim 6:415-427, 2003 Davis EW, Legendre AM: Successful treatment of guttural pouch mycosis with itraconazole and topical enilconazole in a horse. J Vet Intern Med 8:304-305, 1994 Korenek NL, Legendre AM, Andrews FM, et al: Treatment of mycotic rhinitis with itraconazole in three horses. J Vet Intern Med 8:224-227, 1994 Sherman KM, Myhre GD, Heymann EI: Fungal osteomyelitis of the axial border of the proximal sesamoid bones in a horse. J Am Vet Med Assoc 229:16071611, 2006 Tomsa K, Glaus TM, Zimmer C, et al: Fungal rhinitis and sinusitis in three cats. J Am Vet Med Assoc 222:1380-1384, 2003 Orosz SE: Antifungal drug therapy in avian species. Vet Clin Exotic Anim 6:337-350, 2003 Deem SL: Fungal diseases of birds of prey. Vet Clin Exotic Anim 6:363-376, 2003 Perkhofer S, Lass-Florl C, Hell M, et al: The nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mold infection in immunocompromised and/or immunosuppressed patients. Int J Antimicrob Agents 36:531-536, 2010 Tansho S, Abe S, Ishibashi H, et al: Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice. J Infect Chemother 12:355362, 2006 Patterson TF, Fotehrgill AW, Rinaldi MG: Efficacy of itraconaozle solution in a rabbit model of invasive aspergillosis. Antimicrob Agents Chemother 37: 2307-2310, 1993 Beernaert LA, Pasmans F, Van Waeyenberghe L, et al: Avian Aspergillus fumigatus strains resistant to both itraconazole and voriconazole. Antimicrob Agents Chemother 53:2199-2201, 2009 Nagino K, Shimohira H, Ogawa M, et al: Comparison of the therapeutic efficacy of oral doses of fluconazole and itraconazole in a guinea pig model of dermatophytosis. J Infect Chemother 6:41-44, 2000
38. 39. 40.
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44. 45. 46. 47. 48. 49.
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53.
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Greenacre CB: Fungal diseases of ferrets. Vet Clin Exotic Anim 6:435-448, 2003 Moriello KA: Treatment of dermatophytosis in dogs and cats: review of published studies. Vet Dermatol 15:99-107, 2004 Iovannitti C, Negroni R, Bava J, et al: Itraconazole and flucytosine⫹itraconazole combination in the treatment of experimental cryptococcosis in hamsters. Mycoses 38:449-452, 1995 Hanley CS, MacWilliams P, Giles S, et al: Diagnosis and successful treatment of Cryptococcus neoformans variety grubii in a domestic ferret. Can Vet J 47:10151017, 2006 Malik R, Martin P, McGill J, et al: Successful treatment of nasal cryptococcosis in a ferret. Aust Vet J 78:158-159, 2000 Sorensen KN, Sobel RA, Clemons KV, et al: Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob Agents Chemother 44:1512-1517, 2000 Foley JP, Legendre AM: Treatment of coccidioidomycosis osteomyelitis with itraconazole in a horse. A brief report. J Vet Intern Med 6:333-334, 1992 Sharman MJ, Stayt J, McGill SE, et al: Clinical resolution of a nasal granuloma caused by Trichosporon loubieri. J Feline Med Surg 12:345-350, 2010 Hess MO: Phaeohyphomycotic osteomyelitis in the femur of a cat. J Feline Med Surg 11:878-880, 2009 Pawloski DR, Brunker JD, Singh K, et al: Pulmonary Paecilomyces lilacinus infection in a cat. J Am Anim Hosp Assoc 46:197-202, 2010 Winter RL, Lawhon SD, Halbert ND, et al: Subcutaneous infection of a cat by Colletotrichum species. J Feline Med Surg 12:828-830, 2010 Gonzalez-Alonso-Alegre EM, Rodriguez-Alvaro A, Belclaux-Real Del Asua M, et al: Mycotic blepharitis associated with Fusarium species in a Eurasian eagle owl (Bubo bubo hispanus). Vet Rec 159:720721, 2006 Abrams GA, Paul-Murphy J, Ramer JC, et al: Aspergillus blepharitis and dermatitis in a Peregrine falconGyrfalcon hybrid (Falco peregrinus ⫻ Falco rusticolus). J Avian Med Surg 15:114-120, 2001 Forzan MJ, Gunn H, Scott P: Chytridiomycosis in an aquarium collection of frogs: diagnosis, treatment, and control. J Zoo Wildl Med 39:406-411, 2008 Nichols DK, Lamirande EW, Pessier AP, et al: Experimental transmission and treatment of cutaneous chytridiomycosis in poison dart frogs (Dendrobates auratus and Dendrobates tinctorius). IAAAM 31st Annual Conference Proceedings, New Orleans, LA, pp 49-52, 2000 Pare JA, Sigler L, Hunter DB, et al: Cutaneous mycoses in chameleons caused by the Chrysosporium anamorph of Nannizziopsis vriesii (Apinis) Currah. J Zoo Wildl Med 28:443-453, 1997 Hedley J, Eatwell K, Hume L: Necrotizing fungal dermatitis in a group of bearded dragons (Pogona vitticeps). Vet Rec 166:464-465, 2010 Allender MC, Schumacher J, Milam J, et al: Pharmacokinetics of intravascular itraconazole in the American horseshoe crab (Limulus polyphemus). J Vet Pharmacol Ther 31:83-86, 2007
160 56. 57.
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Keller Martin MV: The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J Antimicrob Chemother 44:429-437, 1999 Cross LJ, Bagg J, Aitchison TC: Efficacy of the cyclodextrin liquid preparation of itraconazole in treatment of denture stomatitis: comparison with itraconazole capsules. Antimicrob Agents Chemother 44:425-427, 2000 Talwalker JA, Soetikno RE, Carr-Locke DL, et al: Severe cholestasis related to itraconaozle for the treatment of onychomycosis. Am J Gastroenterol 94: 3632-3633, 1999 Firooz A, Khamesipour A, Dowlati Y: Itraconazole pulse therapy improves the quality of life of patients with toenail onychomycosis. J Dermatolog Treat 14: 95-98, 2003
60. 61.
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Orosz SE, Frazier DL: Antifungal agents: a review of their pharmacology and therapeutic indications. J Avian Med Surg 9:8-18, 1995 Bowman MR, Pare JA, Sigler L, et al: Deep fungal dermatitis in three inland bearded dragons (Pogona vitticeps) caused by the Chrysosporium anamorph of Nannizziopsis vriesii. Med Mycol 45:371376, 2007 Orosz SE, Frazier DL, Schroeder EC, et al: Pharmacokinetic properties of itraconaozle in Blue-fronted amazon parrots (Amazona aestiva aestiva). J Avian Med Surg 10:168-173, 1996 Lumeij JT, Gorgevska D, Woestenborghs R: Plasma and tissue concentrations of itraconazole in racing pigeons (Columba livia domestica). J Avian Med Surg 9:32-35, 1995
Itraconazole Krista A. Keller, DVM
I
traconazole is a synthetic triazole used in both human and veterinary medicine. This antifungal agent works by altering the cellular membranes of fungi, increasing membrane permeability, and allowing cellular content leakage and impaired uptake of pertinent extracellular components.1 Itraconazole has additionally been shown to be an antiangiogenic agent; it inhibits endothelial cell cycle progression at the G1 phase and has been shown to block vascular endothelial growth factor– dependent angiogenesis in vivo. The true potential of the antiangiogenic nature of this drug has not been fully evaluated at this time.2 Several commercially available preparations of itraconazole are marketed in the United States, including itraconazole oral suspension (Sporanox, 10 mg/mL; Janssen Pharmaceuticals, Titusville, NJ USA), itraconazole capsules (Sporanox, 100 mg; Janssen Pharmaceuticals), and injectable itraconazole (Sporanox, 10 mg/ mL; Janssen Pharmaceuticals). Both the oral suspension and the injectable form contain cyclodextrin. Cyclodextrin, or hydroxypropyl-beta-cyclodextrin, is a ring of substituted glucose molecules. The use of cyclodextrin increases the absorption, and thus, the bioavailability of itraconazole.3 After administration of oral itraconazole-cyclodextrin formulations, absorption of cyclodextrin is negligible and the compound is broken down by gastrointestinal microflora to glucose molecules that are then absorbed.3 When itraconazole is administered in the injectable form, cyclodextrin is rapidly cleared by glomerular filtration with little accumulation in the body.3 When taken orally, itraconazole absorption is highly dependent on gastric pH and the formulation used.3-8 Itraconazole suspension, with cyclodextrin, given under fasted conditions has a more rapid absorption and higher bioavailability when compared with patients that have not been fasted.4,8,9 In contrast, itraconazole capsules show higher plasma concentrations when administered at mealtimes.8 This trend for better absorption and higher tissue concentrations with the capsule formulations being administered with food has been confirmed in pi-
156
geons.10 Because of the dependence of itraconazole capsules on low gastric pH, concurrent use of antacids11 and proton pump inhibitors12 are not recommended when using itraconazole. In animal species treated by veterinarians, several studies have evaluated the effect of different formulations of itraconazole on bioavailability and absorption. In penguins, it was found that commercially available itraconazole suspension had superior absorption to compounded itraconazole suspensions that lack cyclodextrin.5 A second study in penguins showed that commercially available capsules were absorbed better than bulk itraconazole powder.6 In a study comparing the pharmacokinetic profiles of 2 commercially available itraconazole formulations in horses (Equus ferus), it was found that administration of the oral suspension resulted in more consistent absorption and higher maximum concentrations when compared with horses administered the capsule formulation.7 On absorption, itraconazole is highly protein bound to blood cells and plasma proteins. Only 0.2% of the drug is found unbound in humans3 and 1.2% in horses.7 Itraconazole is widely distributed to tissues, reaching highest levels in lipophilic tissues such as the skin, sebum, and the female reproductive tract.1,3 Itraconazole is also found in high concentrations in the nails and skin where the drug is incorporated into the matrix of the nail.3 Minimal concentrations of this drug are found in the noninflamed tissues of the aqueous humor of the eye, cerebrospinal fluid, urine, and saliva.1,3,7 From the Department of Clinical Sciences, Louisiana State University, School of Veterinary Medicine, Baton Rouge, LA USA Address correspondence to: Krista A. Keller, DVM, Department of Clinical Sciences, Louisiana State University, School of Veterinary Medicine, Skip Bertman Dr, Baton Rouge, LA 70803. E-mail: [email protected]. © 2011 Elsevier Inc. All rights reserved. 1557-5063/11/2002-$30.00 doi:10.1053/j.jepm.2011.02.012
Journal of Exotic Pet Medicine, Vol 20, No 2 (April), 2011: pp 156 –160
Therapeutic Review
The liver metabolizes itraconazole into several different metabolites, including the active hydroxyitraconazole.1,3 There is significant variation in the metabolism pattern, indicated by the itraconazole: hydroxyitraconazole ratio, in animal species treated by veterinarians. For example, horses have been found to have no measureable levels of plasma hydroxyitraconazole after itraconazole administration,7 whereas pigeons (Columba livia) have been found to have hydroxyitraconazole concentrations higher than itraconazole in tissues.10 The half-life of itraconazole in humans has been reported to be between 21 and 64 hours, and because of its long half-life, steady-state plasma concentrations may not be reached for 6 days in humans,1,3 up to 14 days in red-tailed hawks (Buteo jamaicensis),13 and 21 days in cats (Felis catus).14 Most itraconazole metabolites are excreted through the bile and urine. Unmetabolized itraconazole is not detected in the urine, but 3% to 18% of the dose is detected in the feces.3 Itraconazole and its metabolites have been shown to be cytochrome P450 and P-glycoprotein inhibitors.15,16 Because itraconazole and its metabolites are cytochrome P450 and P-glycoprotein inhibitors, therapy with other medications metabolized by this route must be monitored for signs of toxicity. Specific medications include digoxin,3,17 tacrolimus,18 cyclophosphamide,19 dexamethasone,20 diazepam,21 and oxycodone.22 In some cases, itraconazole is given to therapeutically increase serum levels of medications to reduce the cost of expensive drugs (e.g., cyclosporine).23 Rifampin, when used concurrently with itraconazole, has been shown to decrease therapeutic concentrations of itraconazole in both humans3,24 and animals.25 Fungal disease is the main indication for using itraconazole for therapeutic purposes. Aspergillus spp. represents the underlying etiology of a large percentage of fungal disease cases diagnosed in veterinary medicine. Animals that have been treated successfully for Aspergillus using itraconazole include the guinea pig (Cavia porcellus),26 horses,27-29 and cats.30 Additionally, itraconazole should be considered as a primary drug of choice for the treatment of aspergillosis in birds31,32 and is the treatment of choice for prophylaxis and treatment of aspergillosis in penguins.5 In a recent study, invasive mold infections in immunocompromised and immunosuppressed human patients represented a significant burden on human health care, with 2.36 cases occurring in every 100,000 inhabitants.33 Of those human cases, 67% were from Aspergillus spp.33 Some of what we know regarding the use of itraconazole in nondomestic
157 species was generated from experimental models of invasive pulmonary aspergillosis for humans using laboratory animals. Mice (Mus musculus) and rabbits (Oryctolagus cuniculus) with experimentally induced invasive aspergillosis were found to respond to itraconazole therapy.34,35 Although itraconazole has been an important antifungal in human medicine, the advent of newer azole antifungals has decreased human medicine’s dependence on it, with less than 1% of recently studied patients receiving this therapy alone.33 Despite the heavy reliance of veterinary medicine on itraconazole, several strains of Aspergillus spp. have shown acquired resistance to this drug.36 Itraconazole has been used to manage fungal diseases (other than aspergillosis) in a variety of different domestic and exotic pet mammals. It has been used to successfully eliminate dermatophytosis in guinea pigs,37 ferrets (Mustelus putorious furo),38 dogs (Canis familiaris), and cats39; cryptococcosis in hamsters (Mesocricetus auratus)40 and ferrets41,42; histoplasmosis in ferrets38; blastomycosis in ferrets38; and coccidiodomycosis in rabbits43 and horses.44 Additionally, itraconazole has been used to successfully treat fungal rhinitis,45 fungal osteomyelitis caused by Cladosporium spp.,46 fungal pneumonia,47 and systemic fungal disease by Colletotrichum spp.48 In nonmammalian species, fungal blepharitis and dermatitis were successfully treated in a Eurasian eagle owl (Bubo bubo hispanus) and a Peregrine falcon hybrid (Falco peregrinus ⫻ F. rusticolus).49,50 In reptiles and amphibians, itraconazole has been shown to effectively treat fungal epidemics, including infections with chytrid fungus in amphibians51,52 and Chrysosporium anamorph of Nannizziopsis vriesii in reptiles.53,54 Lastly, itraconazole has been administered to horseshoe crabs (Limulus polyphemus) with an unspeciated fungal disease.55 The most common adverse side effects associated with itraconazole administration in humans are abdominal pain, nausea, vomiting, and dyspepsia.56 In one study, 2/3 of human patients receiving oral itraconazole suffered from a gastrointestinal disorder.57 Liver enzyme concentrations should be monitored during treatment because of potential hepatotoxicity.56 Rarely, cholestasis with accompanying hyperbilirubinemia has been found in humans treated with itraconazole.58 More recently, itraconazole pulse therapy has been evaluated as a way to decrease some of the negative side effects described with itraconazole without sacrificing plasma concentrations and efficacy.59 In veterinary medicine, as with humans, gastrointestinal signs have been noted during itraconazole
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therapy. Raptors are described to have significant anorexia when placed on itraconazole therapy.60 Additionally, bearded dragons (Pogona vitticeps) administered itraconazole at the high end of the dosing range showed significant anorexia and weight loss.61 Hepatotoxicity appears to be more rare in animals treated by veterinarians, but has been described in 2 cats.30,45 Several pharmacokinetics studies have been reported in birds.13,62,63 In blue-fronted Amazon parrots (Amazona aestiva aestiva), the subject birds were gavaged the contents of the commercially available capsules mixed with 0.1 N hydrochloric acid and diluted with orange juice. The study showed that a dose of 5 mg/kg every 24 hours achieved adequate plasma concentrations to be inhibitory to most Aspergillus spp.62 In a pigeon study, the birds were given capsules under fasting conditions. The study showed a dose of 6 mg/kg every 12 hours reached adequate plasma concentrations for treatment of susceptible fungal infections in most tissues outside of the lungs. To reach adequate fungicidal concentrations in the lungs, a dosing regimen of 26 mg/kg every 12 hours was recommended.63 A study in red-tailed hawks found that providing the oral itraconazole suspension at 10 mg/kg every 24 hours was sufficient for treating aspergillosis.13 Captive Humboldt penguins (Spheniscus humboldti) should be dosed at 8.5 mg/kg orally twice per day or 20 mg/kg orally once a day using commercially available capsules to achieve acceptable steady-state therapeutic levels.6 Although a dosing interval was not provided for black-footed penguins (Spheniscus demersus), 7 mg/kg orally of the commercially available itraconazole suspension resulted in adequate therapeutic concentrations.5 The differences noted in the pharmacokinetic studies described above provide scientific evidence that itraconazole doses vary for different animal species and when different formulations of the drug are administered. Consequently, care should be taken when trying to determine a proper dose of itraconazole for a particular patient so that one has the best chance of successfully treating the fungal disease.
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