Pharmacokinetics and Pharmacodynamics of Posaconazole

Abstract

Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

Fig. 1

Antifungal mechanism of action of posaconazole

Fig. 2

Posaconazole distribution depicted as the ratios of tissue or fluid concentrations versus simultaneously measured plasma concentrations in different organs and tissues (tissue concentration unit: ng/g, fluid or plasma concentration unit: ng/mL). CSF cerebrospinal fluid, ELF pulmonary epithelial lining fluid

Fig. 3

Schematic illustration of the pharmacological and physiological processes driving antifungal drug response and how they link to the currently used PK/PD indices. C_max peak concentration, C_min trough concentration, AUC area under the concentration–time curve, MIC minimum inhibitory concentration, GM test detection of galactomannan, G test detection of (1–3)-β-D-glucan, IFD invasive fungal disease