isavuconazole and Renal-Insufficiency

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

Topics: Adult; Antifungal Agents; Fungi; Humans; Immunocompromised Host; Invasive Fungal Infections; Invasive Pulmonary Aspergillosis; Middle Aged; Mucormycosis; Mycoses; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Rare Diseases; Renal Insufficiency; Triazoles

The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD-based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp.

Topics: Antifungal Agents; Area Under Curve; Aspergillus; Candida; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Liver Diseases; Male; Microbial Sensitivity Tests; Monte Carlo Method; Nitriles; Pyridines; Renal Insufficiency; Species Specificity; Triazoles