title: Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.
abstract: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Chudasama
authors.forename: F
authors.initials: F
authors.lastname: Schaedeli Stark
authors.forename: J M
authors.initials: JM
authors.lastname: Harrold
authors.forename: J
authors.initials: J
authors.lastname: Tibbitts
authors.forename: S R
authors.initials: SR
authors.lastname: Girish
authors.forename: M
authors.initials: M
authors.lastname: Gupta
authors.forename: N
authors.initials: N
authors.lastname: Frey
authors.forename: D E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D000882:Haplorhini; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D008956:Models, Chemical; D011159:Population Surveillance / Q000379:methods; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine