SP10-3 Clinical evidence of PK/PD of antifungal drugs

Abstract

After more than 30 years of clinical use, amphotericin B still remains a drug of choice for the treatment of serious infections, despite its toxicity. In the last 15 years, attempts have been made to both reduce its toxicity and improve its solubility without affecting antifungal activity. The encapsulation of amphotericin B into liposomes or other lipid complexes has led to reduced toxicity and has improved its clinical efficacy. Recently, the antifungal armamentarium has been enlarged by the introduction of new and more potent triazoles characterized by a broad spectrum of activity against both yeasts and moulds, as well as by the development of newer drugs with a different mechanism of action on the synthesis of the cell wall, namely the echinocandins: caspofungin, micafungin, and anidulafungin. From a pharmacological point of view, knowledge of both the pharmacodynamics (PD) and pharmacokinetics (PK) of the antifungal drugs ismandatory in order to evaluate the role of the different agents in the clinical setting, and has gained increasing importance for the selection and dosing of different antifungal agents. Like antimicrobial drugs, the various antifungals display static or cidal activity against pathogenic fungi, and may have both an in vitro and in vivo post-antifungal effect (PAFE). Two major PD behaviours of these drugs have been recognized, namely concentration-related and time-related activity. Both the polyenes and the echinocandins are concentration-dependent drugs with predictable dose–exposure relationships; the results obtained from dose fractionation studies suggest that the Cmax/MIC is the best PK–PD parameter with a maximal efficacy for a total drug Cmax/MIC value of 10 and a net inhibitory effect for values near 3. Azole derivatives are concentration-independent drugs and the probability of clinical success is significantly higher when the AUC(free drug)/MIC is ~25. The predominant pharmacokinetic differences among the three echinocandins are volume of distribution, metabolism and half-life. The comparative clinical pharmacokinetic data of triazoles indicate several compound-related differences in absorption, metabolism, tissue distribution and elimination. All triazoles inhibit different cytochromeP450 dependent pathwayswith the consequent potential drug interactions with drugs that are metabolized by the same enzymes. As a consequence, therapeutic drugmonitoring of triazoles (with the partial exclusion of fluconazole) is recommended to ensure efficacy and to avoid or limit toxicity. In conclusion, the enrichment of our armamentarium with newer broad-spectrum triazoles and echinocandins offers clinicians the possibility of choosing from among many effective antifungal drugs. The determination of both their PK and PD properties has provided important new insights into the safe and effective use of these drugs.