A pharmacokinetic rationale for alternate dosing strategies of anidulafungin

Brüggemann, R.J(1)*; Van der Velden, W.J.F.(2); Knibbe, C.A.J.(3); Colbers, A.(1); Hol, S.(1); Burger, D.M.(1); Blijlevens, N.M.A.(2); Donnelly, J.P.(2);


Background: Little is known about the pharmacokinetics (PK) of anidulafungin (ANF) given in alternate dosing strategies other than the standard once daily schedule though these may offer a more convenient way of providing prophylaxis to patients at high risk for invasive fungal diseases. We set out to explore this in a cohort of patients admitted for an allogeneic HSCT or to receive intensive chemotherapy for AML. Methods: We defined two groups of 10 patients that were to receive 200 mg q48h (group 1) or 300 mg q72h ANF (group 2) respectively on the day of HSCT or immediately following chemotherapy. ANF was given at a higher infusion rate of 2mg/min and continued for 14 d. Blood samples were drawn daily. In addition, two PK curves were constructed after 1 and 2 weeks of treatment at 14 predefined time points. ANF was analysed by a validated UPLC-fluorescence method and a population pharmacokinetic model was developed using nonlinear mixed-effects modelling (NONMEM 7.2 ; pirana 2.8). Results: Of 26 patients, 20 (group 1 (n=10: 3F, 7M) and group 2 (n=10: 2F, 8M) had fully evaluable PK. The mean age was 55 yr (range 21-64) and weight 77 kg (range 52-113). A two-compartment model best fitted the data. In the final model the central volume of distribution proved to be dependent on the lean body weight (linear function) and clearance on the concomitant use of cyclosporine A (CsA : dichotomous) ( P?

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