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Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia

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Abstract

Background and Objective

To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody–drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study.

Methods

The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL1) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL1 and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL1 and central volume.

Results and Conclusions

PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m2 on days 1 and 15 versus, 3 mg/m2 fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen.

Study Identifier

0903A1-102-US.

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Acknowledgements

The authors thank Ana Ruiz-Garcia (Pfizer Inc.) for guidance in modeling techniques and review of the manuscript. Editorial support was provided by Susan Reinwald, PhD, and Kevin O’Regan, PhD, of Complete Healthcare Communications, LLC, and David Wateridge, PhD, of Engage Scientific Solutions, and was funded by Pfizer.

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Authors and Affiliations

  1. Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA

    Joanna C. Masters & Beverly Knight

  2. Pfizer Global Product Development Oncology, 300 Technology Square, Suite 302, Cambridge, MA, 02139-3520, USA

    Elly Barry

Authors
  1. Joanna C. Masters
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Corresponding author

Correspondence to Joanna C. Masters.

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Funding

This study was funded by Pfizer Inc. Open-access publication of this manuscript was sponsored by Pfizer.

Conflict of interest

JCM, EB, and BK are full-time employees of Pfizer and have stock ownership.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all patients (or their parent/guardian) included in the 0903A1-102-US study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

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Masters, J.C., Barry, E. & Knight, B. Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia. Clin Pharmacokinet 58, 271–282 (2019). https://doi.org/10.1007/s40262-018-0694-x

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