Efficacy of Extended-Interval Dosing of Micafungin Evaluated Using a Pharmacokinetic/Pharmacodynamic Study with Humanized Doses in Mice

Abstract

The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the echinocandins favor infrequent administration of large doses. The in vivo investigation reported here tested the utility of a range of humanized dose levels of micafungin using a variety of prolonged dosing intervals for the prevention and therapy of established disseminated candidiasis. Humanized doses of 600 mg administered every 6 days prevented fungal growth in prophylaxis. Humanized doses of 300 to 1,000 mg administered every 6 days demonstrated efficacy for established infections.

FIG 1

Prophylaxis study design and in vivo efficacy of micafungin for prevention of invasive candidiasis. (A) Study schematic showing the timing of therapy, infection time points, and study duration. (B) Micafungin prophylaxis data with C. albicans K1. (C) Micafungin prophylaxis data with C. albicans 98-17. The x axis represents the dose level that was humanized in mice. The y axis represents the burden of organisms in mouse kidneys. Each vertical bar represents the mean and standard deviation of data from four mice. Untreated control data are represented by the black vertical bar. Each colored bar represents a different day of infection after micafungin therapy. The solid horizontal line represents the burden of organisms in mice 1 h after infection (net stasis endpoint).

FIG 2

Established infection study design and in vivo efficacy of micafungin for treatment of invasive candidiasis. (A) Study schematic showing the timing of infection and the timing and dosing intervals for micafungin therapy and study duration. (B) Micafungin treatment data with C. albicans K1. (C) Micafungin treatment data with C. albicans 98-17. The x axis represents the dose level that was humanized in mice. The y axis represents the burden of organisms in mouse kidneys. Each vertical bar represents the mean and standard deviation of data from four mice. Untreated control data are represented by the black vertical bar. Each colored bar represents a different dosing interval for micafungin therapy (QD, once a day; Q3D, every 3 days; etc.). The solid horizontal line represents the burden of organisms in mice 1 h after infection (net stasis endpoint).