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

Background. Echinocandins have been used as primary therapy of invasive aspergillosis (IA) with sub-optimal results at standard dosing. We explored the efficacy of dose escalation in a validated in vitro PK/PD model Methods. Six echinocandin WT and three non-WT A. fumigatus isolates were tested in the in vitro PK/PD model simulating anidulafungin, caspofungin and micafungin exposures with fC_max 0.01-16 mg/L and t_1/2=8-22h. The relationship between the fAUC_0-24/MEC and % aberrant mycelia formation was analyzed. PK/PD indices associated with 50-99.99% maximal activity (EI₅₀-EI_99.99) were correlated with the clinical outcome of 50 mg/day standard dose of caspofungin. The probability of target attainment (PTA) was calculated for different dosing regimens of each echinocandin performing Monte Carlo analysis. Results. A sigmoidal PK/PD relationship was found for WT isolates with EI₉₉ 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 irrespectively of their MEC and drug exposure. The EI₉₉, EI_99.9 and EI_99.99 corresponded to 2, 3 and 4 log₁₀ formation of aberrant mycelia and correlated with survival, favorable and complete response rates to caspofungin primary therapy in patients with IA. Very low PTA (Conclusions. Among the three echinocandins, only caspofungin at two-three times licensed dosing was associated with a high PTA. Caspofungin dose escalation might deserve clinical validation.