Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Abstract

Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

“…However, other studies contradicted this conclusion and found a link between the level of antifungal exposure and the susceptibility of clinical Aspergillus fumigatus isolates [ 43 ] or clinical outcome [ 44 ]. A recent French study compared plasma trough concentrations of isavuconazole with the concentration found at the zone of fungal growth inhibition in order to specify the clinical therapeutic threshold [ 45 ]. A concentration of 2 mg/L conferred 52% of the maximum in vitro antifungal activity on Aspergillus fumigatus , similar to that observed with posaconazole at therapeutic dose.…”

Progress of triazole antifungal agent posaconazole in individualized therapy

“…Moderate dose data for posaconazole suspension suggest that TDM is valuable for improving efficacy, assessing treatment failure due to suboptimal drug exposure and minimising possible azole‐induced toxicity 12 . Currently, the main methods for the determination of posaconazole blood concentrations are chromatography, mass spectrometry, bioassay and fluorescence assays 99–102 . Bioassays and fluorometric assays are less commonly used in clinical practice because of their low selectivity and susceptibility to ambient temperature, pH and other conditions.…”

“…12 Currently, the main methods for the determination of posaconazole blood concentrations are chromatography, mass spectrometry, bioassay and fluorescence assays. [99][100][101][102] Bioassays and fluorometric assays are less commonly used in clinical practice because of their low selectivity and susceptibility to ambient temperature, pH and other conditions.…”

Variability of Isavuconazole Trough Concentrations during Longitudinal Therapeutic Drug Monitoring

“…This method allows ISA quantification in plasma from 0.1 to 20 mg/L, with good precision (intra- and inter-day coefficient of variation <15%) and accuracy (intra and inter-day biases ± 15%). ISA Cmin are considered therapeutic in our institution if they are between 2 and 5 mg/L [ 9 , 19 ] and any dose adjustment was left to the discretion of the clinician.…”