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Δευτέρα 19 Μαρτίου 2018

Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata [PublishAheadOfPrint]

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three IV rezafungin dosing regimens: (i) single 400-mg dose, (ii) 400 mg for Week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the non-clinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin dosing regimen. At the MIC90 for C. albicans and C. glabrata, single dose rezafungin 400 mg achieved probabilities of PK-PD target attainment ≥90% through Week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through Week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through Week 6 following administration of the weekly dosing regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin dosing regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.



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