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Itraconazole Drug Level Monitoring

Itraconazole concentration monitoring for patients with serious mycoses

An 20 kg dog was diagnosed with pulmonary and cutaneous blastomycosis by detection of Blastomyces antigen in the urine at 9.6 ng/mL. The patient was treated for six months with FDA approved itraconazole 5 mg/kg once daily. The patient was doing well clinically but the urinary antigen remained elevated at 5.3 ng/mL. The veterinarian asked why the antigen had not cleared.

QUESTION:
What is the most likely reasons for persistent high-level antigenuria?

  • Antimicrobial resistance?
  • Poor adherence to treatment?
  • Poor absorption of itraconazole?

ANSWER:
Poor absorption. Resistance to itraconazole has not been observed in Histoplasma or Blastomyces. Poor adherence to treatment was excluded based on review of prescription refill records. The most likely reason is variable absorption. The itraconazole concentration was 0.7 µg/mL. The veterinarian increased the dosage to 5 mg/kg twice-daily. The itraconazole concentration on his specimen obtained two weeks later was 2.4 µg/mL. The Blastomyces antigen concentration was 0.4 ng/mL three months later.

Itraconazole is the azole of choice for treatment of histoplasmosis and blastomycosis in humans [1, 2] and animals (Sykes, J, Canine and Feline Infectious Diseases). Though fluconazole is often used because of lower cost, it is less effective than itraconazole [1, 2].

The cost of itraconazole can be reduced by using generic FDA approved pelletized itraconazole, which achieves comparable blood concentrations to Sporanox in dogs and cats (Table).  Ranges depicted in the table are based on recommendations of authorities in antifungal drug level monitoring [3] and differ from those in the veterinary publication [4].  

Generic itraconazole and brand name Sporanox capsules contain “pelletized” drug that includes cyclodextrin, which improves solubility and enhances absorption.  Compounded non-FDA approved itraconazole does not contain cyclodextrin, is poorly absorbed and does not achieve therapeutic concentrations.

Itraconazole levels may be quantified by a biological assay (bioassay) which measures its inhibitory effect on growth of a Candida strain in agar plates. The bioassay reflects the combined effect of parent itraconazole and its hydroxy metabolite, both which have antifungal activity. The disadvantage of the bioassay is that may be falsely elevated in patients who are receiving or have recently received other antifungal agents.  Blood levels should be at least 2.0 µg/mL by bioassay. Levels above 10 µg/mL may be toxic and are unnecessary. Levels below 2.0 µg/mL are subtherapeutic.

Levels of itraconazole and its hydroxy metabolite may be obtained by high pressure liquid chromatography (HPLC).  HPLC is available at several reference laboratories and is considerably more expensive than bioassay. Its major advantage is accurate determination of itraconazole level in the presence of other antifungal agents. Only the parent itraconazole is used for assessment of therapeutic levels, and trough levels should be at least 1.0 to 2.0 µg/mL for treatment of fungal infections [3].  

Blood levels are variable and should be determined even when FDA approved formulations are used. Blood levels are almost always subtherapeutic in patients receiving the non-FDA approved compounded formulations offered at some veterinary pharmacies (Table).  These should not be used for systemic fungal infections.

Levels should be measured at steady state, 14 days after initiating therapy or changing the dose in dogs and 21 days in cats.  As itraconazole half-life is long, timing of the specimen after dosing is not critical but trough levels (lowest level of the dosing interval, just before the next dose) are recommended.  The serum specimen should be frozen and shipped with a cold pack for next day or second day delivery to prevent degradation of the drug, causing falsely-low blood levels.

Several options exist if the itraconazole blood level is low.  First, increase the dose and recheck the blood level. Second, switch to another triazole that is recommended for the infection that is being treated.

The FDA approved formulation is available as a fixed dosage capsule containing 100 mg of itraconazole. This dosage may be difficult to use in small animals. Some pharmacies will repackage the capsule to accommodate smaller dosages.

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REFERENCE LIST

(1) Chapman SW, Dismukes WE, Proia LA, et al. Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin Infect Dis 2008 May 5; 460:1801-12.

(2) Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007 Oct 1; 45(7):807-25.

(3) Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009 Jan; 53(1):24-34.

(4) Renschler J, Albers A, Sinclair-Mackling H, Wheat LJ. Comparison of Compounded, Generic, and Innovator-Formulated Itraconazole in Dogs and Cats. J Am Anim Hosp Assoc 2018 Jul; 54(4):195-200.

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