Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): Reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling

The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY30 3366) in plasma were characterized with normal rabbits, and the relationshi ps between drug concentrations and antifungal efficacy were assessed in cli nically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafu ngin demonstrated linear plasma pharmacokinetics that fitted best to a thre e-compartment open pharmacokinetic model. Following administration over 7 d ays, the mean (+/- standard error of the mean) peak plasma concentration (C -max) increased from 0.46 +/- 0.02 mug/ml at 0.1 mg/kg to 63.02 +/- 2.93 mu g/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) rose from 0.71 +/- 0.04 to 208.80 +/- 24 .21 mug . h/ml. The mean apparent volume of distribution at steady state (V -ss) ranged from 0.953 +/- 0.05 to 1.636 +/- 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 +/- 0.01 to 0.149 +/- 0.00 liter/kg/ h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased V-ss at the higher end of the dosage range aft er multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest i n lung and liver (0.85 +/- 0.16 to 32.64 +/- 2.03 and 0.32 +/- 0.05 to 43.7 6 +/- 1.62 mug/g, respectively), followed by spleen and kidney (0.24 +/- 0. 65 to 21.74 +/- 1.86 and <0.20 to 16.92 +/- 0.56, respectively). Measurable concentrations in brain tissue were found at dosages of greater than or eq ual to0.5 mg/kg (0.24 +/- 0.02 to 3.90 +/- 0.25). Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of dis seminated candidiasis and pulmonary aspergillosis based on the Bayesian app roach and model parameters from normal animals as priors revealed a signifi cantly slower clearance (P < 0.05 for all dosage groups) with a trend towar d higher AUC(0-24) values, higher plasma concentrations at the end of the d osing interval, and a smaller volume of distribution (P < 0.05 to 0.193 for the various comparisons among dosage groups). Pharmacodynamic modeling usi ng the residual fungal tissue burden in the main target sites as the primar y endpoint and C-max, AUC(0-24), time during the dosing interval of 24 h wi th plasma drug concentration equaling or exceeding the MIC or the minimum f ungicidal concentration for the isolate, and tissue concentrations as pharm acodynamic parameters showed predictable pharmacokinetic-pharmacodynamic re lationships 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 exp erimental 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 pro mise of improving and accelerating our understanding of the action of antif ungal compounds in vivo.