Abstract
This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) 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 (CLt); and concomitant rituximab treatment was a covariate of the linear clearance component (CL1). 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.
Highlights
Inotuzumab ozogamicin (InO) is a humanized antibody drug conjugate comprising G544, a IgG4 antibody, with a drug-antibody ratio of 6 [1, 2]
Received: 2 June 2017 / Accepted: 8 November 2018 / Published online: 11 March 2019 Ó Pfizer 2019. This population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) 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)
The population PK analysis presented in this manuscript refers to InO concentrations only because total calicheamicin was only available in the NHL studies, and in most samples (91% for NHL and 98% for ALL) unconjugated calicheamicin concentrations were below the lower limit of quantitation (LLOQ)
Summary
Inotuzumab ozogamicin (InO) is a humanized antibody drug conjugate comprising G544, a IgG4 antibody, with a drug-antibody ratio of 6 [1, 2]. InO targets cluster of differentiation 22 (CD22) and all InO molecules are conjugated to N-acetyl-c-calicheamicin, a potent cytotoxic antibiotic, via an acid-labile 4-(40-acetylphenoxy) butanoic. A previous study demonstrated the stability of InO in human plasma and serum, with a rate of hydrolysis of 1.5–2% per day [6, 7]. B-cell acute lymphoblastic leukemia (ALL) was assessed in the phase 3 INO-VATE trial [11]. Results from the study showed that InO was associated with a significantly higher complete remission or complete remission with incomplete
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