title: Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial.
abstract: BACKGROUND
  The exact extent of and the mechanism by which trastuzumab causes cardiac side effects are not completely unravelled. We investigated the (cardiotoxic) side effects of trastuzumab in a relatively large homogeneous population.
  
  
  METHODS
  Healthy male volunteers (n = 54) with a left ventricle ejection fraction (LVEF) > 55% were administered 6 mg/kg trastuzumab (n = 46) IV in 90 min in a placebo-controlled, parallel study. Placebo consisted of 0 · 9% NaCl (n = 8). Assessments included body weight, routine and cardiac laboratory markers and serial echocardiographic examinations (8 placebo and 9 trastuzumab treated participants) up to 63 days after dosing. Statistical analysis was done using repeated measurements of variance.
  
  
  RESULTS
  Following trastuzumab infusion, fluid retention was observed: mean body weight increased over the first 4 days post-administration with 0 · 4 kg (95%-confidence interval: - 0 · 2, 0 · 9, p = 0 · 2261) compared to placebo, mean haemoglobin concentration decreased with 0 · 3 mM (- 0 · 6, - 0 · 1; p = 0 · 0043), as did haematocrit (- 0 · 013 L/L [- 0 · 024, - 0 · 002], p = 0 · 0216), and protein (- 2 g/L [- 4, - 0], p = 0 · 0443) and albumin (- 2 g/L [- 3, - 1], p < 0 · 0001) concentrations. Elevations in NT-proBNP levels, parallel to the weight increase, were observed in individual cases, but not on a group level. Troponin-T concentrations did not increase. The only echocardiographic parameter that changed significantly at all studied dose levels was E/A-ratio, a load-dependent parameter: from 1 · 81 (SD 0 · 42) to 1 · 98 (0 · 31) 3-5 days after administration, contrast to placebo of 0 · 57 (90%-CI: 0 · 21-0 · 93, p = 0 · 0034). Ejection fraction and pulsed-wave Doppler recorded parameters remained unchanged.
  
  
  CONCLUSIONS
  Single dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory) response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients.
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Joannes A A
authors.initials: JA
authors.lastname: Reijers
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
mesh_terms: D000293:Adolescent; D000328:Adult; D001810:Blood Volume / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D054715:Cardiotoxins / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013318:Stroke Volume / Q000187:drug effects*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D054715:Cardiotoxins; D000068878:Trastuzumab
keywords: Cardiotoxicity; Echocardiography; Fluid retention; Haemodynamics; Healthy volunteers; Trastuzumab