title: Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated.
abstract: PURPOSE Pharmacokinetics (PKs) and safety results from phase II/III trials suggest that, if high trastuzumab serum concentrations are reached early during treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, patients will gain clinical benefit, and the synergistic effects of trastuzumab and chemotherapy will be maximized. This phase I/II study evaluated the PKs, efficacy, and safety of a novel, intensive loading regimen of trastuzumab in women with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS An intensive loading regimen of trastuzumab was given (6 mg/kg intravenously on days 1, 8, and 15 followed by 6 mg/kg every 3 weeks from day 22) to women age 18 years or older with HER2-positive MBC who may have received previous surgery, radiotherapy, and/or chemotherapy. Study medication was continued until disease progression or withdrawal occurred. Results All eligible women (N = 72) received at least one dose of trastuzumab. Median estimated trough concentration of trastuzumab at the end of 3 weeks of the intensive loading regimen (total of 18 mg/kg of trastuzumab administered) of cycle 1 was 119 mg/L, which is higher than steady-state trough concentrations with a conventional weekly or every-3-week regimen (64.9 or 47.3 mg/L, respectively). No new or unexpected adverse events or increased cardiotoxicity were reported during the study. In patients with measurable disease (n = 47), response rate was 23.4%. Median time to progression was 7.7 months (in all patients). CONCLUSION An intensive loading regimen of trastuzumab achieved higher-than-steady-state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.
authors.affiliation: Winship Cancer Institute, Emory University, School of Medicine, 1365C Clifton Rd NE, Ste 4014, Atlanta, GA 30322, USA. leyland@emory.edu
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.forename: Ramon
authors.initials: R
authors.lastname: Colomer
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Trudeau
authors.forename: Andrew
authors.initials: A
authors.lastname: Wardley
authors.forename: Jean
authors.initials: J
authors.lastname: Latreille
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Ricardo
authors.initials: R
authors.lastname: Cubedo
authors.forename: Nedal
authors.initials: N
authors.lastname: Al-Sakaff
authors.forename: Andrea
authors.initials: A
authors.lastname: Feyereislova
authors.forename: Olivier
authors.initials: O
authors.lastname: Catalani
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Michael
authors.initials: M
authors.lastname: Brewster
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000097:blood*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D014018:Tissue Distribution; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab