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Open Access 01-02-2020 | Myelodysplastic Syndrome | Original Research Article

Population Pharmacokinetics of an Anti-PD-L1 Antibody, Durvalumab in Patients with Hematologic Malignancies

Authors: Ken Ogasawara, Kathryn Newhall, Stephen E. Maxwell, Justine Dell’Aringa, Vitalina Komashko, Nurgul Kilavuz, Richard Delarue, Myron Czuczman, Lars Sternas, Shelonitda Rose, C. L. Beach, Steven Novick, Simon Zhou, Maria Palmisano, Yan Li

Published in: Clinical Pharmacokinetics | Issue 2/2020

Abstract

Background and Objectives

Durvalumab, a human monoclonal antibody targeting programmed cell death ligand 1, has been approved for urothelial carcinoma and stage III non-small cell lung cancer by the US Food and Drug Administration and is being evaluated in various malignancies. The objective of this study was to develop a population-pharmacokinetic model of durvalumab in patients with various hematologic malignancies and to investigate the effects of demographic and disease factors on the pharmacokinetics in this population.

Methods

A total of 1812 concentrations from 267 patients with myelodysplastic syndromes, acute myeloid leukemia, multiple myeloma, non-Hodgkin lymphoma, or Hodgkin lymphoma were included in the analysis.

Results

The pharmacokinetics of durvalumab was adequately described by a two-compartment model with first-order elimination. A decrease in durvalumab clearance over time was mainly explained by incorporation of time-dependent changes in albumin (in all patients) and immunoglobulin G (in patients with multiple myeloma) into the model. For multiple myeloma, patients with immunoglobulin G ≥ 20 g/L showed a 30% lower area under the concentration–time curve at cycle 1 compared with patients with immunoglobulin G < 20 g/L. The impact of any baseline covariates on durvalumab pharmacokinetics did not appear to be clinically relevant. The pharmacokinetics of durvalumab in hematologic malignancies was generally consistent with previously reported pharmacokinetics in solid tumors.

Conclusions

These results support the same dosing regimen (1500 mg every 4 weeks) for both solid tumors and hematologic malignancies from the perspective of adequate exposure. Additionally, total immunoglobulin G level could be a critical covariate for the pharmacokinetics of monoclonal antibodies in patients with multiple myeloma.

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Title: Population Pharmacokinetics of an Anti-PD-L1 Antibody, Durvalumab in Patients with Hematologic Malignancies
Authors: Ken Ogasawara
Kathryn Newhall
Stephen E. Maxwell
Justine Dell’Aringa
Vitalina Komashko
Nurgul Kilavuz
Richard Delarue
Myron Czuczman
Lars Sternas
Shelonitda Rose
C. L. Beach
Steven Novick
Simon Zhou
Maria Palmisano
Yan Li
Publication date: 01-02-2020
Publisher: Springer International Publishing
Keywords: Myelodysplastic Syndrome
Multiple Myeloma
Acute Myeloid Leukemia
Solid Tumor
Non-Hodgkin Lymphoma
Pharmacokinetics
Hodgkin Lymphoma
Published in: Clinical Pharmacokinetics / Issue 2/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-019-00804-x

At a glance: The STEP trials

Springer Medicine

Population Pharmacokinetics of an Anti-PD-L1 Antibody, Durvalumab in Patients with Hematologic Malignancies

Abstract

Background and Objectives

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusions

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