title: Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia.
abstract: Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.
authors.affiliation: Department of Medicine and Medical Microbiology and Immunology, Section of Infectious Disease, University of Wisconsin, MFCD, Room 5211, 1685 Highland Ave., Madison, WI 53705, USA. dra@medicine.wisc.edu
authors.forename: David
authors.initials: D
authors.lastname: Andes
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hammel
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Varsha
authors.initials: V
authors.lastname: Iyer
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Reynolds
authors.forename: Donald N
authors.initials: DN
authors.lastname: Buell
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kovanda
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
mesh_terms: D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058387:Candidemia / Q000097:blood / Q000188:drug therapy*; D002177:Candidiasis / Q000097:blood / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D054714:Echinocandins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D055666:Lipopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin