title: Comparison of the probability of target attainment of anidulafungin against Candida spp. in patients with acute leukaemia.
abstract: This study aimed to investigate the probability of target attainment (PTA) of various anidulafungin dosing regimens against Candida spp. in patients with acute leukaemia. A Monte Carlo simulation was performed using a previously published population pharmacokinetic model. The following dosing scenarios were evaluated: 200 mg loading dose (LD) on Day 1 then 100 mg daily (manufacturer's recommended dosing regimen); 200 mg LD on Day 1 then 100 mg every 48 h (q48 h); and 200 mg q48 h, 200 mg every 72 h (q72 h) and 300 mg q72 h. For each dosing regimen, free drug concentrations were calculated to evaluate the effect of 99% protein binding. The PTA at various pharmacodynamic (PD) targets was determined as the percentage of subjects who achieved a free drug area under the plasma concentration-time curve over the minimum inhibitory concentration ratio (ƒAUC/MIC) or a free drug maximum plasma concentration over the minimum inhibitory concentration ratio (ƒC(max)/MIC) above the PD targets. PTA expectation values were then calculated for each dosing regimen. The currently recommended dosing regimen of anidulafungin was not optimal for invasive candidiasis in patients with acute leukaemia. Alternate dosing strategies with higher doses and extended dosing intervals (intermittent dosing) achieved better target attainment. This is the first study to optimise therapy with anidulafungin using Monte Carlo simulation. These results provide a rationale in support of future clinical investigation of intermittent dosing of anidulafungin.
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Tan N
authors.initials: TN
authors.lastname: Doan
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Electronic address: david.kong@monash.edu.
authors.forename: David C M
authors.initials: DC
authors.lastname: Kong
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.affiliation: Malignant Haematology and Stem Cell Transplantation Service, Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Walker
authors.affiliation: Malignant Haematology and Stem Cell Transplantation Service, Alfred Health, 55 Commercial Road, Melbourne, Victoria 3004, Australia; Department of Clinical Haematology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Electronic address: carl.kirkpatrick@monash.edu.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
mesh_terms: D000077612:Anidulafungin; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D058387:Candidemia / Q000188:drug therapy*; D054714:Echinocandins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007938:Leukemia / Q000150:complications; D008826:Microbial Sensitivity Tests; D010949:Plasma / Q000737:chemistry*; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D000077612:Anidulafungin
keywords: Acute leukaemia; Echinocandins; Monte Carlo simulation