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

Author: 

Willeman T, Tonini J, Garnaud C, Bailly S, Gandia P, Stanke-Labesque F, Maubon D, Gautier-Veyret E.
Fundam Clin Pharmacol. 2019 Sep 10.

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 A.fumigatus and C. 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: rho=0.942, p<0.0001; C. parapsilosis: rho=0.949, p<0.0001) and POS (rho=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).

KEYWORDS:

bioassay; isavuconazole; pharmacokinetic-pharmacodynamic; posaconazole; therapeutic drug monitoring