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..

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 (E_max) 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.