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372 Gumbo et al.plasma C max ,AUC 0–1 , and dose. However, pharmacokinetic studies in rabbits withlife-threatening disseminated candidiasis revealed a reduction in clearance of anidulafunginin these animals to between 0.05 and 0.08 L/hr/kg, and a smaller volumeof distribution, which was significantly lower than in “healthy” animals. Consequently,infected animals achieved higher AUCs than noninfected animals receivingthe same doses. Furthermore, doses between 0.1 and 1 mg/kg produced nonlinearkinetics in infected rabbits (73).Human PharmacokineticsData on human pharmacokinetics of anidulafungin are scant and have beenmostly published in abstract form (74–78). The data are therefore incomplete anddo not allow a proper examination of the methods employed. The data aresummarized in Table 9. C max and AUC increased linearly with dose (74,78).Metabolism of anidulafungin does not rely upon hepatic microsomal enzymebiotransformation. Nonenzymatic chemical degradation leads to opening of thering to produce a linear peptide, which in turn is degraded in plasma bynonspecific peptidases. In fact, in patients with severe hepatic dysfunction, there issome increase in clearance of drug (Table 9) (76), although mechanisms to explainthis are unclear. Renal dysfunction has no effect on metabolism or elimination ofthe drug. While the plasma t ½ of anidulafungin is approximately one day, that ofits metabolites is five days (77). The entire dose of anidulafungin is eliminated viafecal excretion, 10% as parent drug and 90% as degradants (77). There is thus noneed for dose adjustment in patients with renal failure, with hepatic dysfunction.Human Population pharmacokineticsThe population pharmacokinetics of anidulafungin has been studied in 129patients who were being treated for esophageal candidiasis, 87 patients beingtreated for invasive candidiasis, seven patients being treated for invasive aspergillosis,and two with azole refractory mucosal candidiasis (79). This represents agood mix of patients for whom anidulafungin is likely to be used. Anidulafunginwas administered as daily infusions in three doses: 50, 75, and 100 mg. Steadystateconcentrations were analyzed using a mixed effects model. The data best fit atwo-compartment model with first-order elimination. Clearance of anidulafunginincreased with body weight, diagnosis of invasive candidiasis, and male gender.The percentage relative standard error for weight on clearance was 27% while itwas 25% for gender on clearance. In addition, central volume of distributionincreased with weight. However, the covariates explained only 20% of theTABLE 9 Pharmacokinetics of Single-Dose Anidulafungin in HumansPatient population(no. of patients)Intravenousdose (mg/day)C max(mg/L)AUC 0–1(mg*hr/L)Clearance(L/hr)Terminalt ½ (hr)Mild hepatic impairment (6) 50 2.2 (0.3) – 0.9 (0.2) 34.0(2.5)Severe hepatic impairment (5) 50 1.6 (0.4) 42.4 (9.9) 1.23 (0.3) –Creatinine clearance50 2.3 (0.5) 54.2 (10.9) 1.0 (0.2) –