Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model--authors' response

Sir, In vitro PK/PD relationship between fAUCτ/MIC, Cmax/MIC and %fTτ>MIC and growth inhibition (assessed by galactomannan production) in an in vitro PK/PD model. fAUCτ, area under the free concentration–time curve for dosing interval τ; Cmax, maximum free concentrations, fT, time above the MIC for dosing interval τ; τ, dosing interval 12 h for human twice daily dosing or 24 h for animal once daily dosing schemes. Previous single-dose in vitro studies with the same model showed suppression of galactomannan production only with the dosing regimens with Cmax >4 × MIC.3 In these experiments and further studies that we conducted in our laboratory with the same model, shortly after the concentration of voriconazole fell below the MIC, galactomannan was detected, indicating a short post-antifungal effect (PAFE). These observations are in line with the <3 h PAFE previously observed only after 24 h of exposure at high concentrations.4 The concentration-dependent activity of voriconazole is also in line with previous in vitro studies where fungicidal activity of voriconazole was observed against A. fumigatus isolates at concentrations >3.2-fold higher than the MICs.5,6 We recently analysed the impact of 12- and 24-hourly dosing regimens on azole pharmacodynamics and found that voriconazole pharmacodynamics were not affected by the dosing frequency.7 The magnitude of all three PK/PD indices was similar for the two dosing regimens, as also shown in Figure 1. This was not the case with posaconazole, where dosing frequency had a severe impact on its pharmacodynamics.7 This indicates that increasing the dosing frequency will not increase the antifungal efficacy of voriconazole if the target PK/PD index is not attained. Similarly, regimens of dosing isavuconazole every 24 h and every 8 h were equally effective in an animal model of experimental aspergillosis.8 Of course, since the subject of the study of Siopi et al.2 was not the impact of dosing frequency on voriconazole efficacy, a properly designed study will be required to answer this question definitively. Animal studies of experimental aspergillosis where voriconazole was given once or twice daily showed similar efficacy for the same doses.9,10 In children, because of the high clearance, voriconazole exposure is lower than in adults with the same doses. Thus, higher doses are recommended in order to achieve exposure similar to that in adults. A similar observation has been made for fluconazole.11 As shown in this letter, splitting the daily dose into three or four doses over the same period may not increase antifungal efficacy if the fAUC/MIC target is not attained. None to declare.