Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-beta-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis

122

The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 g/ml at 0.5 mg/kg to 16.8 g/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 g ⅐ h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 g/g), liver (2.05 to 8.82 g/g), spleen (1.87 to 9.05 g/g), and kidney (1.40 to 6.12 g/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 g/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.Micafungin (FK463) is a novel, semisynthetic antifungal echinocandin-like lipopeptide that inhibits the synthesis on 1,3␤-glucan, an essential polymeric polysaccharide in the cell wall of many pathogenic fungi (12, 24). As a class, the echinocandins lack mechanism-based toxicity and have an extended spectrum of antifungal activity without cross-resistance to existing antifungal agents (4,5,9,15,18). In vitro, micafungin has demonstrated potent and broad-spectrum fungicidal activity against clinically relevant Candida spp. and potent inhibitory activity against Aspergillus spp. (21, 23, 25). The compound displayed promising antifungal efficacy in murine models of disseminated candidiasis as well as disseminated and pulmonary aspergillosis (16,19,20) and is currently in advanced stages of clinical development (12).Little is still known, however, about the disposition of micafungin in plasma and tissues. Therefore, the purpose of this study was to assess the compartmental plasma pharmacokinetics and tissue distribution of micafungin at potentially therapeutic dosages in healthy laboratory animals. The inform...

Section: Discussionmentioning

confidence: 99%

Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits

Groll

Mickiene

Petraitis

et al. 2001

122

“…Across species, the disposition of cilofungin was characterized by a very short half-life, a small V, negligible tissue accumulation, and inconsistent efficacy in animal models of susceptible opportunistic mycoses after single-dose administration (18). Increased antifungal efficacy, particularly in the brain, could be achieved only through intermittent and continuous administration of high daily dosages that elicited nonlinear saturable plasma pharmacokinetics with sustained plasma and tissue drug concentrations (2,25,30,32).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to cilofungin (32), caspofungin (16), and micafungin (17), VER is fungicidal against most Candida spp. in vitro with predominantly concentration-dependent activity in concentration response and time course experiments (9,14,21,22,28,35).…”

Section: Discussionmentioning

confidence: 99%

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

Groll

Mickiene

Petraitienė

et al. 2001

130

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 ...

“…Walsh et al. (32) showed a direct correlation between the concentrations of cilofungin in tissue and antifungal activity in a rabbit model of disseminated candidiasis. The continuous and intermittent infusion dosage regimens of cilofungin that elicited nonlinear saturation pharmacokinetics in plasma were associated with increased antifungal activity against experimental candidiasis in granulocytopenic rabbits (32).…”

mentioning

confidence: 99%

“…The mortality with combination therapy of amphotericin B and cilofungin was higher than that with amphotericin B alone and with cilofungin alone. Members of the echinocandin class of 1,3-p-glucan synthesis inhibitors, including cilofungin, also exhibit activity against Pneumocystis carinii (26,32).…”

mentioning

confidence: 99%

Comparative efficacies of cilofungin (Ly121019) and amphotericin B against disseminated Candida albicans infection in normal and granulocytopenic mice

Khardori

Nguyen

Stephens

et al. 1993

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 X 106 CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 106 CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80%o when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 106 CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50%o was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 105 and 1 x 105 intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 105 C. albicans. Mice infected with 105 C. albicans and treated with cilofungin (25 mg/kg)