Abstract
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.
Similar content being viewed by others
References
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.
Enoch DA, Ludlam HA, Brown NM. Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006;55:809–18.
Pfaller MA, Pappas PG, Wingard JR. Invasive fungal pathogens: current epidemiological trends. Clin Infect Dis. 2006;43:S3–14.
Rybak JM, Marx KR, Nishimoto AT, Rogers PD. Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent. Pharmacotherapy. 2015;35:1037–51.
Kim S, Kwon J, Park C, Han S, Yim D, Choi J, et al. Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether B-cyclodextrin in haematological patients with renal impairment. Mycoses. 2016;59:644–51.
Moore JN, Healy JR, Kraft WK. Pharmacologic and clinical evaluation of posaconazole. Expert Rev Clin Pharmacol. 2015;8:321–34.
Natesan SK, Chandrasekar PH. Isavuconazole for the treatment of invasive Aspergillosis and Mucormycosis: current evidence, safety, efficacy, and clinical recommendations. Infect Drug Resist. 2016;9:291–300.
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.
Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR III, et al. Isavuconazole treatment for Mucormycosis: a single-arm open-label trial and case–control analysis. Lancet Infect Dis. 2016;16:828–37.
Thompson GR III, Rendon A, Riberio dos Santos R, Queiroz-Telles F, Ostrosky-Zeichner L, et al. Isavuconazole treatment of Cryptococcosis and dimorphic mycoses. Clin Infect Dis. 2016;63:356–62.
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.
Jacobs SE, Saez-Lacy D, Wynkoop W, Walsh TJ. Successful treatment of allergic bronchopulmonary aspergillosis with isavuconazole: care report and review of the literature. Open Forum Infect Dis. 2017;4:ofx040.
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.
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.
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.
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.
Kovanda LL, Marty FM, Maertens J, Desai AV, Lademacher C, Engelhardt M, et al. Impact of mucositis on absorption and systemic drug exposure of isavuconazole. Antimicrob Agents Chemother. 2017;61:1–10.
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.
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.
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.
Townsend RW, Akhtar S, Alcorn H, Berg JK, Kowalski DL, Mujais S, Desai AV. Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics. Eur J Clin Pharmacol. 2017;73:669–78.
Knoll BM. Pharmacokinetics of oral isavuconazole in a patient after Roux-en-Y gastric bypass surgery. J Antimicrob Chemother. 2014;69:3441–3.
Kovanda LL, Kolamunnage-Dona R, Neely M, Maertens J, Lee M, Hope WW. Pharmacodynamic of isavuconazole for invasive mold disease: role of galactomannan for real-time monitoring of therapeutic response. Clin Infect Dis. 2017;64:1557–63.
Keirns J, Desai A, Kowalski D, Lademacher C, Mujais S, Parker B, et al. QT interval shortening with isavuconazole: in vitro and in vivo effects on cardiac repolarization. Clin Pharmacol Ther. 2017;101:782–90.
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.
Schwartz IS, Wiederhold NP. Update on therapeutic drug monitoring of antifungals for the prophylaxis and treatment of invasive fungal infections. Curr Fungal Infect Rep. 2017;11:75–83.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr. Kyle Wilby reports no conflicts of interest.
Funding
No funding was received for this manuscript.
Rights and permissions
About this article
Cite this article
Wilby, K.J. A Review of the Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole. Eur J Drug Metab Pharmacokinet 43, 281–290 (2018). https://doi.org/10.1007/s13318-017-0445-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13318-017-0445-7