Methods: Published population PK models [J Clin Pharmacol 2004; 44:590-598, ICAAC 2008; Abstr A-011, Antimicrob Agents Chemother 2013; 57:1664-1671] were used to conduct Monte Carlo simulations (n=2000). The intravenous dosing regimens evaluated were anidulafungin 200 mg followed by 100 mg daily (q24h), micafungin 100 mg q24h, and caspofungin 70 mg followed by 50 mg q24h. Individual free-drug plasma AUC values from time zero to 24 h (AUC0-24) were calculated for each agent on Days 1 to 14. MIC values for each agent were assigned to simulated patients individually based on C. glabrata MIC distributions [ICAAC 2015; Abstr M-849]. Free-drug plasma AUC024:MIC targets associated with 1-log10 CFU reductions from baseline of C. glabrata for anidulafungin (32), micafungin (9.45), and caspofungin (13.5), derived from neutropenic murine disseminated candidiasis models, were used [Antimicrob Agents Chemother 2010; 54:2497-2506]. Percent probabilities of PK-PD target attainment were computed on each day of therapy for each dosing regimen. Additional regimens were assessed to identify PK-PD optimized dosing regimens.
Results: Across Days 1 to 14, percent probabilities of PK-PD target attainment were ≤5.40, ≥48.9, and ≥94.4% for the FDA-approved anidulafungin, micafungin, and caspofungin dosing regimens, respectively (Figure). Anidulafungin doses providing high probabilities of PK-PD target attainment were above the maximum dose studied in clinical trials. Percent probabilities ≥87.6% were achieved for micafungin 200 mg followed by 150 mg q24h.
Conclusion: These analyses revealed disparities among FDA-approved echinocandin dosing regimens for candidemia when examined from a PK-PD perspective in the context of C. glabrata. Anidulafungin and micafungin dosing regimens were found to be suboptimal while the caspofungin regimen yielded high percent probabilities of PK-PD target attainment.
J. C. Bader,
S. Bhavnani, None
P. G. Ambrose, None
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