Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation

Objectives: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC. 5000 for non-parapsilosis Candida sp. and >= 285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. Methods: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. Results: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was <= 25 g/L and CL decreased by 25% when SOFA score was >= 10. Body weight was related to CL, Vc and Vp by allometric models. PTA was >= 90% in Candida albicans and Candida glabrata infections, except when the MIC was >= 0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC >= 0.5 mg/L. Conclusions: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs >= 0.015 mg/L.