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Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial.

Reijers JA, Burggraaf J - EBioMedicine (2015)

Bottom Line: Troponin-T concentrations did not increase.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Human Drug Research, Leiden, The Netherlands.

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.

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.

No MeSH data available.


Related in: MedlinePlus

Time profile.Time profiles of safety parameters in a 22 year old healthy male, who received 6 mg/kg trastuzumab.
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f0010: Time profile.Time profiles of safety parameters in a 22 year old healthy male, who received 6 mg/kg trastuzumab.

Mentions: The time course of a selection of parameters after infusion of 6 mg/kg Herceptin® in a 22 year old healthy male is depicted in Fig. 2. A clear decline in erythrocyte concentration (and related parameters, like haemoglobin and haematocrit) characterises the first 2–4 days post-administration, with a return to baseline between 8 and 63 days post-dose. This decline was paralleled by a decrease in protein and albumin concentration, whereas body weight and NT-proBNP level increased.


Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial.

Reijers JA, Burggraaf J - EBioMedicine (2015)

Time profile.Time profiles of safety parameters in a 22 year old healthy male, who received 6 mg/kg trastuzumab.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563119&req=5

f0010: Time profile.Time profiles of safety parameters in a 22 year old healthy male, who received 6 mg/kg trastuzumab.
Mentions: The time course of a selection of parameters after infusion of 6 mg/kg Herceptin® in a 22 year old healthy male is depicted in Fig. 2. A clear decline in erythrocyte concentration (and related parameters, like haemoglobin and haematocrit) characterises the first 2–4 days post-administration, with a return to baseline between 8 and 63 days post-dose. This decline was paralleled by a decrease in protein and albumin concentration, whereas body weight and NT-proBNP level increased.

Bottom Line: Troponin-T concentrations did not increase.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Human Drug Research, Leiden, The Netherlands.

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.

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.

No MeSH data available.


Related in: MedlinePlus