Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

Abstract

IntroductionBecause of the high mortality of invasive fungal infections (IFIs), appropriate exposure to antifungals appears to be crucial for therapeutic efficacy and safety.Materials and methodsThis review summarises published pharmacokinetic data on systemically administered antifungals focusing on co-morbidities, target-site penetration, and combination antifungal therapy.Conclusions and discussionAmphotericin B is eliminated unchanged via urine and faeces. Flucytosine and fluconazole display low protein binding and are eliminated by the kidney. Itraconazole, voriconazole, posaconazole and isavuconazole are metabolised in the liver. Azoles are substrates and inhibitors of cytochrome P450 (CYP) isoenzymes and are therefore involved in numerous drug–drug interactions. Anidulafungin is spontaneously degraded in the plasma. Caspofungin and micafungin undergo enzymatic metabolism in the liver, which is independent of CYP. Although several drug–drug interactions occur during caspofungin and micafungin treatment, echinocandins display a lower potential for drug–drug interactions. Flucytosine and azoles penetrate into most of relevant tissues. Amphotericin B accumulates in the liver and in the spleen. Its concentrations in lung and kidney are intermediate and relatively low myocardium and brain. Tissue distribution of echinocandins is similar to that of amphotericin. Combination antifungal therapy is established for cryptococcosis but controversial in other IFIs such as invasive aspergillosis and mucormycosis.

Impact of voriconazole plasma concentrations on treatment response in critically ill patients

“…Voriconazole has non‐linear pharmacokinetics, is subject to wide interindividual variability and is metabolized in the liver through cytochrome CYP2C19, CYP2C9 and to a lesser extent also by CYP3A4 . Many studies have shown that several factors can affect the plasma concentrations of voriconazole, including the baseline status of the patients, liver function, inflammation, genetic polymorphism and multiple pharmacological interactions …”

“…8 Many studies have shown that several factors can affect the plasma concentrations of voriconazole, including the baseline status of the patients, liver function, inflammation, genetic polymorphism and multiple pharmacological interactions. [9][10][11] Several authors have demonstrated the relationship between low plasma concentrations of voriconazole and the risk of therapeutic failure, as well as the association between high concentrations and hepatotoxicity and neurological toxicity. [12][13][14][15][16] However, there are few data on the variability of voriconazole concentrations in the critically ill patient.…”

Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation

“…Isavuconazole is slowly metabolized in the liver by CYP3A4 and CYP3A5 isoenzymes. 15 Renal excretion of unchanged isavuconazole accounted for less than 1% of the dose administered. 16 For patients with hepatic or renal impairment, metabolism and elimination may be altered.…”

Docking, Synthesis, Spectral Characterization, and Evaluation of In Vitro Antifungal Activity of Bis/Monophenyl‐1‐aryl‐1H‐tetrazole‐5‐carboxylate

“…The potential scientific challenge is to develop antifungal drugs to cure these diseases, which involve huge investment and long duration . There are six major drugs used for the treatment of systematic infections, which are amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and caspofungin . Some antifungal drugs have face limitations, such as low drug activity, detrimental side effect, negative interaction with other drugs, and inappropriate for oral administration .…”