Clinical Pharmacodynamic (PD) Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Ref ID: 19266

Author:

D. R. Andes, D. K. Reynolds, S. A. Van Wart, A. Lepak, L. L. Kovanda, S. Bhavnani

Author address:

Univ. of Wisconsin, Madison, WI; ICDP, Latham, NY; ICPD, Latham, NY; Astellas Pharma Global Dev., Northbrook, IL

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Echinocandins are a 1st line therapy for candidiasis. Preclinical studies demonstrate the importance of the Cmax/MIC and AUC/MIC as the PD drivers of efficacy. However, few data are available to discern the impact due to PD indices from clinical studies. The current study examines the PD relationship for efficacy for 2 multicenter, randomized trials of micafungin in which dosing regimens varied both dose level and dosing interval. Methods: Host, micafungin exposure, and outcome variables were gathered from 2 Phase 3 trials in which patients were treated for esophageal candidiasis. The 2 micafungin regimens compared were 150 mg QD and 300 mg QOD for 14-21 days. It was hypothesized that use of the higher but less frequently administered regimen would be associated with either superior or equivalent efficacy based upon achieving a higher Cmax and similar AUC, respectively. Both endoscopic microbiologic and histopathologic success at the end of therapy (EOT) and relapse two weeks after EOT were considered. Outcomes were compared for the treatment groups using the 967;2 test or the Fisher exact test. A population PK model was developed for micafungin using data from the 53 patients who received the two dosing regimens of interest. Results: Mycological response at EOT was
observed in 78.8% in the 150mg QD group and 87.1% in
the 300mg QOD group (p=0.056). The treatment
outcomes for the two regimens were also similar for the
relapse endpoint, (failure 12.2% in the QD group and 5.6%
in the QOD arm, p=0.051). Steady-state AUC0-48h for the
dosing regimens were comparable. The median Cmax was
1.65-fold higher while the median Cmin was 0.49-fold lower
for the 300 mg than for the 150 mg group
(p<0.0001). Conclusions: The dose escalation and dosing interval clinical PD analysis is congruent with preclinical studies demonstrating the importance of AUC/MIC and Cmax/MIC. There was a numerically higher efficacy rate in the higher dose, extended interval arm. These provide a rationale for future clinical investigation of higher echinocandin doses and extended dosing intervals.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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