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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Vicuron Pharmaceuticals, King of Prussia, Pennsylvania (Dr. Dowell, Dr. Stogniew, Dr. Krause, Dr. Henkel) and GloboMax, Hanover, Maryland (Dr. Knebel, Dr. Ludden).
The objective of this analysis was to describe the pharmacokinetic characteristics of anidulafungin in patients with serious fungal disease based on pharmacokinetic data collected during four recently completed or ongoing Phase II/III clinical studies. A total of 600 anidulafungin plasma samples from 225 patients across the four studies were available for analysis. Patients received daily intravenous infusions of 50, 75, or 100 mg anidulafungin, preceded by a loading dose that was twice the daily dose. The analysis population consisted of 129 patients with esophageal candidiasis, 87 with invasive candidiasis, 7 with invasive aspergillosis, and 2 with azole refractory mucosal candidiasis. A population analysis approach was used to develop a steady-state pharmacokinetic model for anidulafungin, assess the significance of possible covariates, and determine the amount of intersubject and random residual variability. A two-compartment model with first-order elimination provided the best fit to the data. The clearance of anidulafungin was influenced by weight and gender, and subjects in the invasive candidiasis study had a typical clearance that was approximately 30% higher than subjects from other studies. Weight was determined to be a predictor of the central volume of distribution. The covariates on clearance accounted for less than 20% of the intersubject variability and therefore are deemed to be of little clinical relevance. There was no evidence that the presence of rifampin or metabolic substrates, inhibitors, or inducers of cytochrome P450 influenced the clearance of anidulafungin. This indicates that dosing adjustments are not necessary when anidulafungin is administered in the presence of medications falling into these classifications.
Key Words: Anidulafungin • pharmacokinetics • echinocandin antifungal • clearance
Address for reprints: James A. Dowell, PhD, Vicuron Pharmaceuticals, 455 South Gulph Road, King of Prussia, PA 19406.
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