title: Integrated Two-Analyte Population Pharmacokinetic Model for Antibody-Drug Conjugates in Patients: Implications for Reducing Pharmacokinetic Sampling.
abstract: An integrated pharmacokinetics (PK) model that simultaneously describes concentrations of total antibody (Tab) and antibody-conjugated monomethyl auristatin E (acMMAE) following administration of monomethyl auristatin E (MMAE)-containing antibody-drug conjugates (ADCs) was developed based on phase I PK data with extensive sampling for two ADCs. Two linear two-compartment models that shared all parameters were used to describe the PK of Tab and acMMAE, except that the deconjugation rate was an additional clearance pathway included in the acMMAE PK model compared to Tab. Further, the model demonstrated its ability to predict Tab concentrations and PK parameters based on observed acMMAE PK and various reduced or eliminated Tab PK sampling schemes of phase II data. Thus, this integrated model allows for the reduction of Tab PK sampling in late-phase clinical development without compromising Tab PK characterization.
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.affiliation: QuantPharm LLC, North Potomac, Maryland, USA.
authors.forename: L
authors.initials: L
authors.lastname: Gibiansky
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Dere
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Chu
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hirata
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Genentech Inc, South San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Girish
mesh_terms: D003198:Computer Simulation; D054796:Drug Dosage Calculations; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008954:Models, Biological; D008962:Models, Theoretical; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004364:Pharmaceutical Preparations
chemical_list: D018796:Immunoconjugates; D009842:Oligopeptides; D004364:Pharmaceutical Preparations; C495575:monomethyl auristatin E