Dataset Information

Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response.

ABSTRACT:

Background.

The ability to make early therapeutic decisions when treating invasive aspergillosis using changes in biomarkers as a surrogate for therapeutic response could significantly improve patient outcome.

Methods.

Cox proportional hazards model and logistic regression were used to correlate early changes in galactomannan index (GMI) to mortality and overall response, respectively, from patients with positive baseline GMI (≥0.5) and serial GMI during treatment from a phase 3 clinical trial for the treatment of invasive mold disease. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with isavuconazole plasma concentrations was conducted to establish the exposure necessary for GMI negativity at the end of therapy.

Results.

The study included 158 patients overall and 78 isavuconazole patients in the PK/PD modeling. By day 7, GMI increases of >0.25 units from baseline (3/130 survivors; 9/28 who died) significantly increased the risk of death compared to those with no increase or increases <0.25 (hazard ratio, 9.766; 95% confidence interval [CI], 4.356-21.9; P < .0001). For each unit decrease by day 7 from baseline, the odds of successful therapy doubled (odds ratio, 2.154; 95% CI, 1.173-3.955). An area under the concentration-versus-time curve over half-maximal effective concentration (AUC:EC50) of 108.6 is estimated to result in a negative GMI at the end of isavuconazole therapy.

Conclusions.

Early trends in GMI are highly predictive of patient outcome. GMI increases by day 7 could be considered in context of clinical signs to trigger changes in treatment, once validated. Our data suggest that this improves survival by 10-fold and positive outcome by 3-fold. These data have important implications for individualized therapy for patients and clinical trials.

Clinical trials registration.

NCT00412893.

SUBMITTER: Kovanda LL

PROVIDER: S-EPMC5434340 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response.

Kovanda Laura L LL Kolamunnage-Dona Ruwanthi R Neely Michael M Maertens Johan J Lee Misun M Hope William W WW

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20170601 11

<h4>Background.</h4>The ability to make early therapeutic decisions when treating invasive aspergillosis using changes in biomarkers as a surrogate for therapeutic response could significantly improve patient outcome.<h4>Methods.</h4>Cox proportional hazards model and logistic regression were used to correlate early changes in galactomannan index (GMI) to mortality and overall response, respectively, from patients with positive baseline GMI (≥0.5) and serial GMI during treatment from a phase 3 c ...[more]

PMID: 28472247

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Project description:Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug-drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug-drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

Dataset Information

Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response.

Background.

Methods.

Results.

Conclusions.

Clinical trials registration.

Publications

Pharmacodynamics of Isavuconazole for Invasive Mold Disease: Role of Galactomannan for Real-Time Monitoring of Therapeutic Response.

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