A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole
Invasive fungal infections are a major cause of morbidity and mortality, especially for immunocompromised patients. Treatment options are few and most are limited by safety and formulation concerns. Isavuconazole is a new triazole antifungal agent with official indications for the treatment of invasive fungal infections caused by Aspergillus and Mucormycosis. Its clinical efficacy has been proven in two landmark trials, SECURE and VITAL. This review aims to summarize and evaluate the published literature reporting clinical pharmacokinetic and pharmacodynamic outcome data of isavuconazole in humans. Data from healthy volunteers demonstrated high oral bioavailability, high hepatic metabolism, and an extended elimination half-life. Data from diseased patients confirmed these findings and also consistently demonstrated that regular dosing of isavuconazole results in achievement of concentrations and exposures that meet pharmacodynamic targets for therapeutic efficacy. Additionally, it was found that renal dysfunction, and mucositis do not majorly affect pharmacokinetic or pharmacodynamic outcomes yet further study is required for severe hepatic and gastric impairment. Future studies should further attempt to understand dose and concentration response relationships, investigate the role (if any) of therapeutic drug monitoring, and strive to optimize dosing in special populations.
Compliance with Ethical Standards
Conflict of interest
Dr. Kyle Wilby reports no conflicts of interest.
No funding was received for this manuscript.
- 1.World Health Organization. The top 10 causes of death. Global Disease Burden. World Health Organization. 2017. http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 14 Sept 2017.
- 8.Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387:760–9.CrossRefPubMedGoogle Scholar
- 11.Viljoen J, Azie N, Schmitt-Hoffmann AH, Ghannoum M. A phase 2, randomized, double-blind, multicenter trial to evaluate the safety and efficacy of three dosing regimens of isavuconazole compared with fluconazole in patients with uncomplicated esophageal candidiasis. Antimicrob Agents Chemother. 2015;59:1671–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Schmitt-Hoffmann A, Roos B, Heep M, Schleimer M, Weidekamm E, Brown T, et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 mg) and oral administrations (100, 200, and 400 mg) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50:279–85.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Schmitt-Hoffmann A, Roos B, Maares J, Heep M, Spickerman J, Weidekamm E, et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50:286–93.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Townsend R, Kato K, Hale C, Kowalski D, Lademacher C, Yamazaki T, et al. Two phase I, open-label, mass balance studies to determine the pharmacokinetics of 14C-labeled isavuconazonium sulfate in healthy male volunteers. Clin Pharmacol Drug Dev. 2017;. https://doi.org/10.1002/cpdd.376.PubMedCentralGoogle Scholar
- 16.Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ. Safety and pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother. 2015;59:2078–85.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Desai A, Kovanda L, Kowalski D, Lu Q, Townsend R, Bonate PL. Population pharmacokinetics of isavuconazole from phase 1 and phase 3 (SECURE) trials in adults and target attainment in patients with invasive injections due to Aspergillus and other filamentous fungi. Antimicrob Agents Chemother. 2016;60:5483–91.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kovanda LL, Desai AV, Lu Q, Townsend RW, Akhtar S, Bonate P, Hope WW. Isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease (results from the VITAL study). Antimicrob Agents Chemother. 2016;60:4568–76.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Schmitt-Hoffmann A, Roos B, Spickermann J, Heep M, Peterfai E, Edwards DJ, Stoeckel K. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother. 2009;53:4885–90.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Kaindl T, Engelhardt M, Townsend R, et al. Intra-subject variability and exposure-response relationship of isavuconazole in the phase 3 SECURE study in patients with invasive mould disease caused by Aspergillus spp. and other filamentous fungi. Abstract O424. Presented at European Society of Clinical Microbiology and Infectious Diseases (ECCMID) 26th Congress, 9–12 April 2016, Amsterdam, Netherlands.Google Scholar