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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

Participant flow diagram.Flow of participants: enrolment was sequential in one of five groups (see main body); echocardiographic examinations were available for groups 1–4, laboratory results and body weight data were available for groups 2–5. Cohorts marked with an asterisk were not analysed, although baseline effects were included in the secondary analysis on the extended dataset (see main body). BS biosimilar product of trastuzumab.
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f0005: Participant flow diagram.Flow of participants: enrolment was sequential in one of five groups (see main body); echocardiographic examinations were available for groups 1–4, laboratory results and body weight data were available for groups 2–5. Cohorts marked with an asterisk were not analysed, although baseline effects were included in the secondary analysis on the extended dataset (see main body). BS biosimilar product of trastuzumab.

Mentions: The trial was a single-centre study of parallel design that consisted of a placebo-controlled double-blind dose escalation scheme (Fig. 1, groups 1–4), and an open-label single-dose bio-equivalence part (Fig. 1, group 5) (Wisman et al., 2014). In total, 118 male volunteers, aged 18–45 years inclusive, who were deemed healthy after a full medical screening, were enrolled sequentially in one of five groups. All had a left ventricle ejection fraction (LVEF) > 55%, measured with echocardiography. The study was approved by an accredited local (BEBO, Assen, The Netherlands) and national independent medical ethics committee (CCMO, The Hague, The Netherlands), and registered under NL37452·056·11/EudraCT 2011-002972-17. Each participant provided written informed consent.


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

Reijers JA, Burggraaf J - EBioMedicine (2015)

Participant flow diagram.Flow of participants: enrolment was sequential in one of five groups (see main body); echocardiographic examinations were available for groups 1–4, laboratory results and body weight data were available for groups 2–5. Cohorts marked with an asterisk were not analysed, although baseline effects were included in the secondary analysis on the extended dataset (see main body). BS biosimilar product of trastuzumab.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: Participant flow diagram.Flow of participants: enrolment was sequential in one of five groups (see main body); echocardiographic examinations were available for groups 1–4, laboratory results and body weight data were available for groups 2–5. Cohorts marked with an asterisk were not analysed, although baseline effects were included in the secondary analysis on the extended dataset (see main body). BS biosimilar product of trastuzumab.
Mentions: The trial was a single-centre study of parallel design that consisted of a placebo-controlled double-blind dose escalation scheme (Fig. 1, groups 1–4), and an open-label single-dose bio-equivalence part (Fig. 1, group 5) (Wisman et al., 2014). In total, 118 male volunteers, aged 18–45 years inclusive, who were deemed healthy after a full medical screening, were enrolled sequentially in one of five groups. All had a left ventricle ejection fraction (LVEF) > 55%, measured with echocardiography. The study was approved by an accredited local (BEBO, Assen, The Netherlands) and national independent medical ethics committee (CCMO, The Hague, The Netherlands), and registered under NL37452·056·11/EudraCT 2011-002972-17. Each participant provided written informed consent.

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