title: Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma.
abstract: Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Stroh
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Winter
authors.affiliation: Pharsight Consulting Services, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Marchand
authors.affiliation: Pharsight Consulting Services, Marseille, France.
authors.forename: L
authors.initials: L
authors.lastname: Claret
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Eppler
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ruppel
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: O
authors.initials: O
authors.lastname: Abidoye
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Teng
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Lin
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dayog
authors.affiliation: Pharsight Consulting Services, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: Bruno
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Girish
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000594389:atezolizumab