Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059

Abstract

Background and objective: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL.

Methods: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data.

Results: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 10³ ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants.

Conclusions: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.

Fig. 1

Inotuzumab ozogamicin pharmacokinetic model structure. Total clearance (CL_total) is the sum of linear clearance (CL₁) and time-dependent clearance (CL_t). CL₂ initial value of time-dependent clearance, IV intravenous, k_des decay coefficient, Q intercompartment clearance, V₁ volume of distribution in the central compartment, V₂ volume of distribution in the peripheral compartment

Fig. 2

Distribution of interindividual variability on the decay coefficient (k_des) from the previously developed adult model after re-estimation versus (a) adult and children population and (b) age categories, the red solid line is the reference line (y = 0)

Fig. 3

Distribution of decay coefficient of the time-dependent clearance versus age in patients with B-cell precursor acute lymphoblastic leukemia. The blue dotted lines are the LOESS

Fig. 4

Goodness-of-fit diagnostic plots of the final model for pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL). Log observed inotuzumab ozogamicin concentration versus a population prediction and b individual prediction. The solid lines show the reference line (y = x). c Scatter plots of conditional weighted residuals against population prediction and d time after each dose

Fig. 5

Prediction-corrected and variability-corrected visual predictive checks in a pediatric B-cell precursor acute lymphoblastic leukemia population. Black circles represent the observed data. The black lines show the median (solid) and the 10th and 90th percentiles (dash) of the observed data. The shaded regions show the 95% confidence interval of the median (red) and the 10th and 90th percentiles (blue) of the simulated concentration (N = 1000). hrs hours

Fig. 6

Distribution of interindividual variability on the decay coefficient (k_des) from the final model versus a the adult and children population and b age categories, the red solid line is the reference line (y = 0)

Fig. 7

Estimation of inotuzumab ozogamicin exposure in pediatric patients with B-cell precursor acute lymphoblastic leukemia using the final model and dosing record in the trial. (a) Cumulative area under the concentration–time curve (AUC) at the end of cycle 1 for non-responders and responders. (b) Cumulative AUC at the end of each cycle 1 for minimal residual disease (MRD)-positive and MRD-negative patients

Fig. 8

Simulation of inotuzumab ozogamicin (InO) in adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL). a Simulated concentration–time profile for four cycles. Green lines denote InO exposure in pediatric patients and red lines denote InO exposure in adults. Medians are shown with dashed lines, the 10th and 90th percentiles are shown with solid lines. b Cumulative area under the concentration–time curve (AUC) at the end of each cycle