A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
- 1.8k Downloads
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts.
A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet–time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM® 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters.
The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet–time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model.
This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet–time profiles, and the ~8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.
KeywordsTrastuzumab emtansine T-DM1 Thrombocytopenia Population pharmacokinetic/pharmacodynamic model Semimechanistic Cumulative TCP
The study was funded by Genentech, Inc. Support for third-party writing assistance was provided by Genentech, Inc.
- 3.Burris HA III, Rugo H, Vukelja SJ et al (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405. doi: 10.1200/JCO.2010.29.5865 PubMedCrossRefGoogle Scholar
- 4.Krop I, LoRusso P, Miller KD et al (2010) A phase II study of trastuzumab-DM1 (T-DM1), a novel HER2 antibody-drug conjugate, in patients with HER2+ metastatic breast cancer who were previously treated with an anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab. Presented at European Society for Medical Oncology Congress, October 8–12, Milan, Italy (abstract 277O)Google Scholar
- 5.Gupta M, LoRusso PM, Wang B et al (2011) Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Pharmacol. doi: 10.1177/0091270011403742 Google Scholar
- 10.Joerger M, Huitema AD, Richel DJ et al (2007) Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 13:6410–6418. doi: 10.1158/1078-0432.CCR-07-0064 PubMedCrossRefGoogle Scholar
- 13.Beal SL, Boeckman AJ, Sheiner LB (1992) NONMEM users guide, part IV. Regents of California, San Francisco. ftp://nonmem.iconplc.com/Public/nonmem720/guides/iv.pdf. Accessed 16 Dec 2011
- 15.Hurvitz SA, Dirix L, Kocsis J et al (2011) Trastuzumab emtansine (T-DM1) versus trastuzumab + docetaxel in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/BO21976). Presented at European Multidisciplinary Cancer Congress, September 23–27, Stockholm, Sweden (abstract 5001)Google Scholar
- 16.Perry MC, McKinney MF (2008) Chemotherapeutic agents: trastuzumab (herceptin). In: Perry MC (ed) The chemotherapy source book, 4th edn. Lippincott Williams & Wilkins, Philadelphia, p 629Google Scholar
- 21.Galsky MD, Eisenberger M, Moore-Cooper S et al (2008) Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol 26:2147–2154. doi: 10.1200/JCO.2007.15.0532 PubMedCrossRefGoogle Scholar
- 22.O’Shaughnessy JA, Venzon DJ, Gossard M et al (1995) A phase I study of sequential versus concurrent interleukin-3 and granulocyte-macrophage colony-stimulating factor in advanced breast cancer patients treated with FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy. Blood 86:2913–2921PubMedGoogle Scholar
- 24.National Cancer Institute (2006) Common terminology criteria for adverse events v3.0 (CTCAE). http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 20 June 2011