Making sense of itraconazole pharmacokinetics

J Antimicrob Chemother. 2005 Sep:56 Suppl 1:i17-i22. doi: 10.1093/jac/dki220.

Abstract

The triazole, itraconazole, has a wide spectrum of antifungal activity in vitro. Confirming this activity in vivo has been a long and difficult task because of problems with formulation, delivery and uncertainty about effective bioavailability. The physicochemical properties of the drug make it insoluble in water but strongly protein bound. The absorption and blood levels of the original capsular formulation were predictable with non-linear, saturation kinetics in normal volunteers. Tissue penetration was high and sustained. In neutropenic patients with haematological malignancies, levels were very variable and the doses required to achieve effective antifungal levels were higher than predicted from normal subjects' results. The solubility of the drug and predictability of blood levels were improved by the formulation of an oral solution with cyclodextrin. Wash-out times were prolonged in patients with this new formulation implying that tissue penetration was maintained. A high volume of distribution suggests that loading may be necessary. An intravenous cyclodextrin solution is also now available allowing rapid loading and avoidance of the well-known gut side effects of the oral solution. Clinical studies have suggested minimum bioavailable dosage and minimum trough blood levels for effective prophylaxis against systemic fungal infection. Interactions are also now well documented and manageable. The drug can be measured reliably, quickly and comparatively cheaply by HPLC in serum and plasma. The frequency of such testing in clinical practice depends on the need to ensure adequate levels and to avoid unwanted toxicity.

Publication types

  • Review

MeSH terms

  • Animals
  • Antifungal Agents / pharmacokinetics*
  • Biological Availability
  • Clinical Trials as Topic
  • Cyclodextrins
  • Drug Interactions
  • Hematologic Neoplasms / metabolism
  • Humans
  • Itraconazole / administration & dosage
  • Itraconazole / adverse effects
  • Itraconazole / blood
  • Itraconazole / pharmacokinetics*
  • Mycoses / drug therapy
  • Mycoses / prevention & control

Substances

  • Antifungal Agents
  • Cyclodextrins
  • Itraconazole