Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial
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 ventricl...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-08-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396415300086 |
| _version_ | 1818313712954507264 |
|---|---|
| author | Joannes A.A. Reijers Jacobus Burggraaf |
| author_facet | Joannes A.A. Reijers Jacobus Burggraaf |
| author_sort | Joannes A.A. Reijers |
| collection | DOAJ |
| description | 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.
Findings: 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.
Interpretation: 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. |
| first_indexed | 2024-12-13T08:38:07Z |
| format | Article |
| id | doaj.art-1a752f556fc94723bae7b58cbdd56d03 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T08:38:07Z |
| publishDate | 2015-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-1a752f556fc94723bae7b58cbdd56d032022-12-21T23:53:36ZengElsevierEBioMedicine2352-39642015-08-012895395910.1016/j.ebiom.2015.05.002Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled TrialJoannes A.A. ReijersJacobus BurggraafBackground: 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. Findings: 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. Interpretation: 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.http://www.sciencedirect.com/science/article/pii/S2352396415300086TrastuzumabFluid retentionCardiotoxicityHaemodynamicsEchocardiographyHealthy volunteers |
| spellingShingle | Joannes A.A. Reijers Jacobus Burggraaf Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial EBioMedicine Trastuzumab Fluid retention Cardiotoxicity Haemodynamics Echocardiography Healthy volunteers |
| title | Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial |
| title_full | Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial |
| title_fullStr | Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial |
| title_full_unstemmed | Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial |
| title_short | Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial |
| title_sort | trastuzumab induces an immediate transient volume increase in humans a randomised placebo controlled trial |
| topic | Trastuzumab Fluid retention Cardiotoxicity Haemodynamics Echocardiography Healthy volunteers |
| url | http://www.sciencedirect.com/science/article/pii/S2352396415300086 |
| work_keys_str_mv | AT joannesaareijers trastuzumabinducesanimmediatetransientvolumeincreaseinhumansarandomisedplacebocontrolledtrial AT jacobusburggraaf trastuzumabinducesanimmediatetransientvolumeincreaseinhumansarandomisedplacebocontrolledtrial |