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.

Keywords: aspergillosis; biomarker; galactomannan; isavuconazole; isavuconazonium sulfate..

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Predicted galactomannan index (GMI) mean profile from the joint model with treatment as a covariate in the longitudinal component for the overall population. Time = day 0 is the time when a patient died (cases) or had last follow-up alive (controls). GMI values were predicted at each day before event (death/alive). Negative values correspond to days before event.

Figure 2.

Change in galactomannan (GM) index at day 7 from baseline for patients who died (11) and survived (11) (overall population).

Figure 3.

Observed galactomannan index (GMI) mean profile for each treatment group (isavuconazole [ISAV] and voriconazole [VORI]) in the longitudinal component. Time = day 0 is the time when a patient died (cases) or had last follow-up alive (controls). Mean GMI values were computed at each day before event (death/alive). Negative values correspond to days before event.

Figure 4.

Predicted mean galactomannan index (GMI) profile at the end of therapy (EOT) for patients with a successful overall response (black line) and those who failed treatment (dashed line). Time 0 represents the assessment day (EOT) (overall population).

Figure 5.

Inhibitory sigmoid maximum effect (Emax) curve demonstrating the pharmacokinetic/pharmacodynamic relationship of isavuconazole area under the concentration-versus-time curve over half-maximal effective concentration (AUC:EC50) and galactomannan index (GMI) values at the end of treatment (terminal GMI). Logistic regression resulted in an r2 of 0.237. Solid line represents the sigmoid curve fit of the model to the data, black squares represent the observed GMI values for each patient, and GMI negative value is included as a dotted line.