In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

Abstract

The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with C max values of 7, 3.5, and 1.75 mg/liter and a t 1/2 of 6 h. The area under the galactomannan index-time curve (AUC GI ) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC 0-24 -AUC GI followed a sigmoid pattern (global R 2 ‫؍‬ 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC 0-24 (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. terreus (F test; P < 0.0001). Target attainment for 3, 4, and 5 mg/kg-of-body-weight voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage. Invasive aspergillosis is the most serious infection caused by Aspergillus species, particularly in patients with hematological malignancies or bone marrow transplantation (16). These infections are characterized by high morbidity and mortality despite available antifungal therapy (7), among which voriconazole is the drug of choice (24). Several factors may influence the clinical outcome, related to the host (underlying condition and immunosuppression), drug (timing of administration and suboptimal exposure), and pathogen (resistance and virulence). Although voriconazole-resistant isolates have been described, their low prevalence (Ͻ10%) cannot explain the high mortality of these infections (10, 21). Testing of large sets of Aspergillus isolates showed that more than half of them exhibited similar in vitro susceptibilities to voriconazole, with a MIC of 0.5 mg/liter (5, 17). Furthermore, the most frequently isolated species, A. fumigatus, A. flavus, and A. terreus, demonstrated similar in vitro susceptibilities, although in vivo experimental and clinical data show that the efficacy of voriconazole differs for these species (22)(23)(24)26). T...

Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an In Vitro Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

“…The conidial suspension was inoculated in the IC, where it remained trapped together with the galactomannan (molecular mass of 20 kDa to 60 kDa) produced by the growing mycelia, while nutrients and drug diffused freely between the IC and EC. The concentration of the galactomannan increased with fungal growth, as found previously (20). After inoculation of the IC, the drug was injected into the EC and IC (for rapid equilibration between the two compartments) every 24 h, and its concentration declined over time, with a half-life (t 1/2 ) observed in human serum after intravenous administration of amphotericin B.…”

Optimization of Polyene-Azole Combination Therapy against Aspergillosis Using an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…To estimate fungal growth and the antifungal effect of each monotherapy and combination dosing regimen, 100-l aliquots from inoculated dialysis tubes were sampled at regular intervals for up to 72 h. The GM index levels were determined in the 100-l samples after adding 200-l saline to reach a final volume of 300 l using a commercially available sandwich enzyme-linked immunoassay (Platelia Aspergillus EIA; Bio-Rad Laboratories), and a GM index-time profile was constructed. Moreover, the area under the GM index curve (AUC GI ) was determined as a surrogate marker of fungal growth, as previously described (14). The percentage of growth inhibition at each dose was calculated as follows: 1 Ϫ AUC GI,DR /AUC GI,GC , where AUC GI,DR is the AUC GI at a certain dose for drug monotherapies and their combination, whereas AUC GI,GC is the AUC GI of the drug-free control.…”

Achieving Target Voriconazole Concentrations More Accurately in Children and Adolescents

“…Third, even single concentrations can be used to estimate entire time-concentration profiles, so that AUC becomes a viable target. This is relevant for voriconazole, as the trough concentration is really only a surrogate for AUC, which is the likely driver of voriconazole efficacy (12)(13)(14)(15).…”

“…Numerous reports of studies in both adults (1)(2)(3)(4)(5)(6)(7), including a prospective randomized trial (8), and children (9)(10)(11) have documented improved outcomes when trough concentrations are maintained above 1 mg/liter, which is a readily measured clinical surrogate for the full area under the concentration-time curve (AUC) that drives efficacy (12)(13)(14)(15).…”