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- Title
Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.
- Authors
Li, Chunze; Wang, Bei; Lu, Dan; Jin, Jin; Gao, Yuying; Matsunaga, Kiyoshi; Igawa, Yuriko; Nijem, Ihsan; Lu, Michael; Strasak, Alexander; Chernyukhin, Nataliya; Girish, Sandhya; Jin, Jin Y
- Abstract
Purpose: 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.Methods: 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.Results: 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.Conclusions: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.
- Subjects
ANTIBODY-drug conjugates; TRASTUZUMAB; HER2 gene; BREAST cancer; PHARMACOKINETICS; THROMBOCYTOPENIA; ASIANS; HEPATOTOXICOLOGY; DISEASE risk factors; DISEASES; THERAPEUTICS; ANTINEOPLASTIC agents; BIOLOGICAL models; BREAST tumors; CELL receptors; CLINICAL trials; DOSE-effect relationship in pharmacology; ETHNIC groups; METASTASIS; MONOCLONAL antibodies; TREATMENT effectiveness
- Publication
Cancer Chemotherapy & Pharmacology, 2016, Vol 78, Issue 3, p547
- ISSN
0344-5704
- Publication type
Academic Journal
- DOI
10.1007/s00280-016-3099-2