Comparative Pharmacodynamics of Echinocandins against Aspergillus fumigatus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model That Correlates with Clinical Response to Caspofungin Therapy: Is There a Place for Dose Optimization?

Abstract

Echinocandins have been used as primary therapy of invasive aspergillosis (IA), with suboptimal results at standard dosing. Here, we explored the efficacy of dose escalation in a validated in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. Six echinocandin wild-type (WT) and three non-WT A. fumigatus isolates were tested in an in vitro PK/PD model simulating anidulafungin, caspofungin, and micafungin exposures with a free drug maximum concentration (fC(max)) of 0.01 to 16 mg/liter and a half-life (t(1/2)) of 8 to 22 h. The relationship between the area under the dosing interval time-free drug concentration curve (fAUC(0-24))/minimum effective concentration (MEC) and % aberrant mycelium formation was analyzed. PK/PD indices associated with 50 to 99.99% maximal activity (El(50) to El(99.99)) were correlated with the clinical outcome of a 50-mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin via Monte Carlo analysis. A sigmoidal PK/PD relationship was found for WT isolates with El(99) values of 766, 8.8, and 115 fAUC(0-24)/CLSI MEC for anidulafungin, caspofungin, and micafungin, respectively. No aberrant mycelia were observed for non-WT isolates, irrespective of their MEC and drug exposure. The El(99), El(99.9), and El(99.99) values corresponded to 2-, 3-, and 4-log 10 formation of aberrant mycelia and correlated with survival, favorable, and complete response rates to caspofungin primary therapy in patients with IA. A very low PTA (= 90% was found with 100 and 150 mg/day of caspofungin and 1,400 mg/day micafungin against WT isolates. For anidulafungin, the PTA for 1,500 mg/day was 10%. Among the three echinocandins, only caspofungin at 2 or 3 times the licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.