The Role of New Posaconazole Formulations in the Treatment of Candida albicans Infections: Data from an In Vitro Pharmacokinetic-Pharmacodynamic Model

Abstract

Background. Posaconazole is more in vitro active against Candida albicans than fluconazole and approved for the treatment of oropharyngeal candidiasis but not invasive candidiasis (IC). We explored the efficacy of posaconazole against C. albicans in an in vitro pharmacokinetic-pharmacodynamic (PK-PD) model of IC and determined the probability of pharmacodynamic target attainment for the oral solution (o.s.) and i.v./tablet formulations. Methods. Three clinical C. albicans isolates (posaconazole MICs 0.008-0.25 mg/liter) were studied in the in vitro PK-PD dilution model simulating steady state posaconazole PK. The in vitro exposure-effect relationship fAUC_0-24/MIC was described and compared with in vivo outcome in animals with IC. PK-PD susceptibility breakpoints and trough levels required for optimal treatment were determined for EUCAST and CLSI24h/48h methods, using the fAUC_0-24/MIC associated with half-maximal activity (EI₅₀) and Monte Carlo simulation analysis for o.s. (400 mg q12h) and i.v./tablet formulations (300 mg q24h). Results. The in vitro mean (95%CI) EI₅₀ was 330 (183-597) fAUC_0-24/MIC for CLSI24h and 169 (92-310) for EUCAST/CLSI48h methods, which are close to the near-stasis in vivo effect. The probability of target attainment for EI50 was estimated and for the wild-type isolates (MIC ≤ 0.06 mg/liter) it was low for the o.s. and higher than 95% for the i.v./tablet formulations for the EUCAST/CLSI48h but not for CLSI24h method. Non-wild-type isolates with EUCAST/CLSI48h MICs 0.125 and 0.25 mg/liter would require trough levels >1.2 and >2.4 mg/liter, respectively. Conclusion. Posaconazole i.v./tablet formulations may have a role in the therapy of invasive infections by wild-type C. albicans isolates provided a steady state is reached fast. A PK-PD susceptibility breakpoint at the ECOFF of 0.06 mg/liter was determined.