Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma

Abstract

This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CL t ) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymphoma (NHL). Pharmacokinetic data included 8361 InO concentration–time observations that were modeled using nonlinear mixed-effects analysis. Covariate relations were identified using generalized additive modeling on base model parameters and then tested in a stepwise manner via covariate modeling. InO concentration was described with a 2-compartment model with linear and time-dependent clearance components. Based on the final model, baseline body surface area was a covariate of the linear and time-dependent clearance components and volume of distribution in the central compartment; baseline percentage of blasts in the peripheral blood was a covariate of the decay coefficient of the time-dependent clearance term (CL t ); and concomitant rituximab treatment was a covariate of the linear clearance component (CL 1 ). The magnitude of change of each pharmacokinetic parameter due to these covariates was not considered clinically relevant. Therefore, no dose adjustment of InO for the treatment of patients with R/R B-cell ALL or NHL is needed on the basis of selected covariates. Electronic supplementary material The online version of this article (10.1007/s10928-018-9614-9) contains supplementary material, which is available to authorized users.

Inotuzumab Ozogamicin for Relapsed/Refractory Acute Lymphoblastic Leukemia in the INO-VATE Trial: CD22 Pharmacodynamics, Efficacy, and Safety by Baseline CD22

“…Across CD22 positivity quartiles as assessed by local laboratories, the exposure to InO was similar and the proportions of patients with dose reduction or dose delay were comparable (Supplementary Table 1). Furthermore, analysis of population pharmacokinetics of InO showed that for patients with R/R B-ALL, CD22 expression (baseline percentage of leukemic blasts expressing CD22 in peripheral blood) was not retained as a covariate of InO distribution and elimination in the final model (24). Therefore, in this current analysis, InO exposure was not assessed as a function of CD22 positivity as assessed by the central laboratory.…”

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series

“…Dosing is usually calculated according to the body weight for patients below one year of age and/or below 10 kg for cytotoxic chemotherapeutic agents, to avoid high exposure due to the relatively high BSA in infants compared to body weight and due to impaired drug elimination. BSA and percentage of blasts in the peripheral blood are covariates that may be important predictors of variability in InO distribution and target‐mediated clearance 11 . InO dosing in our series was based on BSA; although in some children dose reductions were applied, this did not result in increased toxicity.…”

Characterization of the Relationship of Inotuzumab Ozogamicin Exposure With Efficacy and Safety End Points in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

“…Efficacy (CR/CRi and MRD‐negativity) and safety (see Supplementary Material ) end points were monitored. Individual pharmacokinetic (PK) parameters were estimated using a previously reported InO population PK model 6 . InO exposure parameters were calculated for the time of event, or for the duration of treatment if no response was achieved, and included: maximum observed concentration prior to response ( C maxevent ), maximum observed concentration for the duration of treatment ( C maxoverall ), cumulative area under the concentration‐time curve (cAUC), average plasma concentration ( C avg ), and cumulative area under the concentration‐time curve in the first cycle of treatment (cAUCP1).…”