Dataset Information

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

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.

SUBMITTER: Ogasawara K

PROVIDER: S-EPMC7007418 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Ogasawara Ken K Newhall Kathryn K Maxwell Stephen E SE Dell'Aringa Justine J Komashko Vitalina V Kilavuz Nurgul N Delarue Richard R Czuczman Myron M Sternas Lars L Rose Shelonitda S Beach C L CL Novick Steven S Zhou Simon S Palmisano Maria M Li Yan Y

Clinical pharmacokinetics 20200201 2

<h4>Background and objectives</h4>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 th ...[more]

PMID: 31332669

Similar Datasets

Project description:BackgroundThe prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies.ObjectivesThis study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies.DesignThis real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018).MethodsTMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records.ResultsIn 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04).ConclusionTMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies.Trial registrationClinicalTrials.gov NCT02478931.

Dataset Information

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

Background and objectives

Methods

Results

Conclusions

Publications

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

Similar Datasets

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