title: Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.
abstract: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities.
  
  
  
  Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy.
  
  
  
  NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population.
  
  
  
  These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA. li.chunze@gene.com.
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Quantitative Solutions, Menlo Park, CA, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsunaga
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Igawa
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Ihsan
authors.initials: I
authors.lastname: Nijem
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strasak
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Chernyukhin
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity; D005260:Female; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008954:Models, Biological; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: Antibody–drug conjugate; Ethnic sensitivity; Metastatic breast cancer; Pharmacokinetics; T-DM1; Trastuzumab emtansine