In Vivo Characterization of the Pharmacodynamics of Flucytosine in a Neutropenic Murine Disseminated Candidiasis Model

Abstract

In vivo pharmacodynamic parameters have been characterized for a variety of antibacterial agents. These parameters have been studied in correlation with in vivo outcomes in order to determine (i) which dosing parameter is predictive of outcome and (ii) the magnitude of that parameter associated with efficacy. Very little is known of the pharmacodynamics of antifungal agents. We used a neutropenic murine model of disseminated candidiasis to correlate the pharmacodynamic parameters ( Groups of mice were treated with fourfold escalating total doses of 5-FC ranging from 1.56 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Increasing doses produced minimal concentration-dependent killing ranging from 0 to 0.9 log 10 CFU/kidneys. 5-FC did, however, produce a dosedependent suppression of growth after levels in serum had fallen below the MIC. The fungistatic dose increased from 6 to 8 mg/kg with dosing every 3 and 6 h to 70 mg/kg at with dosing every 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Time above the MIC was the parameter best predictive of outcome, while AUC/MIC was only slightly less predictive (time above MIC, R 2 ‫؍‬ 85%; AUC/MIC, R 2 ‫؍‬ 77%; peak level/MIC, R 2 ‫؍‬ 53%). Maximal efficacy was observed when levels exceeded the MIC for only 20 to 25% of the dosing interval. If one considers drug kinetics in humans, these results suggest reevaluation of current dosing regimens.

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

“…Furthermore, studies evaluating 5FC bioavailability and half-life in serum and tissue highlighted a multiple-dose daily regimen. [31][32][33] Although increasing the administration frequency raises concerns about toxicity, 5FC has been used experimentally as an antifungal agent at doses up to 200 mg kg À1 every 6 h for 7 days without signs of toxicity. 35 The current regimen of 500 mg kg À1 four times a day for 4 days did not reveal any signs of toxicity, and permitted a correlation between maximal 5FC bioavailability and high level expression of CD::UPRT at the tumor.…”

“…[19][20][21][22] Meanwhile, other studies demonstrated that the half-life of 5FC was B40 min and that 5FC freely diffused into tissue, [31][32][33] suggesting that after 160 min (that is, four halflives), only 6% of the initial 5FC dose would be present at the tumor. Therefore, an adapted treatment regimen was designed to maximize the bioavailability of CD::UPRT enzyme at the tumor (Figure 5a).…”

Direct Comparison of the Pharmacodynamics of Four Antifungal Drugs in a Mouse Model of Disseminated Candidiasis Using Microbiological Assays of Serum Drug Concentrations

“…Raising the drug concentration to the saturation level which corresponded to serum mMIC for azoles and serum MIC for amphotericin B and maintaining this saturation level appears to be necessary for maximal efficacy. Previous dose fractionation studies have missed this single dose-independent efficacy (2,3,4,7,14). Although saturation levels were comparable to the serum mMIC or MIC in the present study, they should be validated further in models with different infection sites, inoculum sizes, dosing protocols, and additional strains of C. albicans, as in the present study, only one strain of C. albicans was examined.…”

Current Concepts in Antifungal Pharmacology

“…76 Experimental studies in animals and clinical studies with fluconazole in the treatment of mucosal and invasive candidiasis suggest that achieving a serum free-drug AUC:MIC ratio of greater than 25 is the parameter most closely linked to successful treatment. [76][77][78] Although less data are available for other triazoles and mold infections, studies in animal models of aspergillosis also suggest that the AUC:MIC ratio is the best predictor of treatment response to posaconazole, with 50% survival at total-drug AUC:MIC ratios of 100 to 150 and maximal responses at a ratio greater than 440 (free-drug AUC:MIC ratio of approximately 8-25). 79,80 Clinical trial data for candidal infections have suggested that this pharmacokinetic-pharmacodynamic relationship may be helpful for predicting treatment efficacy in For personal use.…”