Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin (LY303366): Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling

Abstract

The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. . Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of disseminated candidiasis and pulmonary aspergillosis based on the Bayesian approach and model parameters from normal animals as priors revealed a significantly slower clearance (P < 0.05 for all dosage groups) with a trend toward higher AUC 0-24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P < 0.05 to 0.193 for the various comparisons among dosage groups). Pharmacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and C max , AUC 0-24 , time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r 2 , 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.Anidulafungin (VER-002 or VER; formerly LY303366) is an investigational, water-soluble, semisynthetic antifungal echinocandin B derivative. It acts by inhibiting the synthesis of ␤-(1,3)-D-glucan, a major structural cell wall polymer of many opportunistic fungi. Disruption of glucan biosynthesis leads to cell wall damage and organism-dependent cell death (7,23). Preclinical studies have demonstrated potent and non-crossresistant activity of VER against medically important fungi both in vitro and in vivo (12,19).Little is known, however, about the disposition of this compound in plasma and tissues and the relationships among dosage, concentrations in the body, and antifungal efficacy in vivo. The purpose of our investigations was therefore twofold: first, to characterize the compartmental pharmacokinetics of VER in plasma over a broad dosage range in normal animals and to design an optimal plasma sampling approach, and second, to assess the implementation of optimal plasma sampling in clinically applicable persistently neutropenic infection models of disseminated candidiasis and invasive pulmonary aspergillosis in order to investigate the relationships of drug concentrations in plasma and tissues to ...

Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlations of the Concentration- and Dose- Dependent Interactions between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis

“…Dowell et al demonstrated that the pharmacokinetics of anidulafungin and voriconazole were not affected by coadministration in normal human volunteers (5). The exposure of anidulafungin in normal rabbits, as described by Groll and colleagues (7), is similar to that of rabbits treated with combination therapy AFG5ϩVRC, which also was the more effective antifungal regimen. Animals treated with the less active single agent AFG5 had higher circulating concentrations.…”

Determination of Fungicidal Activities against Yeasts and Molds: Lessons Learned from Bactericidal Testing and the Need for Standardization

“…Studies of neutropenic rabbits (Candida and Aspergillus), guinea pigs (Aspergillus), and mice (Candida), using residual fungal tissue burden in the main target sites (kidneys, liver, spleen, and lungs) as the primary end point and C max (peak concentration in serum), AUC (area under the concentration curve), time above the MIC or MFC, and tissue concentration as pharmacodynamic end points, have clearly documented the in vivo fungicidal activity of the echinocandins (anidulafungin, caspofungin, and micafungin) against Candida and the lack thereof of these agents against Aspergillus despite improved survival and lung infarct score (2,25,32,62,64,65,72,85). Conversely, the new triazoles (posaconazole, ravuconazole, and voriconazole), when tested in these models, show primarily fungicidal activity against Aspergillus and fungistatic (decreased organ clearance) activity against Candida (2,11,31,33,63,72).…”

“…However, given the fact that most serious fungal infections occur in profoundly immunosuppressed individuals, it is generally assumed that a "cidal" regimen would be preferable in that setting as well (2,9,25,39,47,57,66,73).…”

In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole

“…Anidulafungin is an investigational echinocandin with potent fungicidal activity against many species of Candida (1,4,5,6,11,12,13,14,17,18). Anidulafungin is now in phase III clinical trials and has been shown to be safe and efficacious in treating invasive candidiasis (8).…”