Herceptin
trastuzumab
Species
Monkey
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rhesus and cynomolgus monkey
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Why that species
Monkey HER2 recognized (high homology, similar tissue binding); rodent p185neu not recognized
“rodent p185neu (corresponding receptor protein to human p185HER2) is not recognised, whereas in non-human primates trastuzumab recognises a receptor (as yet uncharacterised) in epithelial cells.”
Surrogate molecule
Yes: surrogate antibody specific for rat c-erbB2, used for rat doxorubicin cardiotoxicity model
“Enhanced cardiotoxicity was not observed in a rat model of doxorubicin cardiotoxicity following addition of a surrogate antibody specific for rat c-erbB2.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Pivotal GLP studies
4-week rhesus monkey; 12- and 26-week cynomolgus monkey repeat-dose studies
“The repeated-dose toxicity evaluation of trastuzumab is based on a four-week study in rhesus monkeys and 12- and 26-week studies in cynomolgus monkeys.”
Route in tox
IV
“In intravenous embryo-fetal development studies in cynomolgus monkeys after repeated administration, the fetal serum levels were 10-33% of the respective maternal concentrations.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, E. coli, human lymphocyte chromosome aberration and mouse micronucleus; all negative
“The in-vivo test was a mouse micronucleus assay involving single iv injection of trastuzumab at 29.5, 59 and 118 mg/kg. All tests gave clearly negative results.”
Carcinogenicity
Not conducted
“Herceptin has not been tested for carcinogenic potential.”
Reproductive & developmental
Cynomolgus monkey fertility, embryo-fetal and peri/postnatal studies: no effects on menstrual cycles, embryo-fetal or neonatal toxicity
“Reproductive function: No effects on menstrual cycles or sex hormone profiles Embryotoxicity: No maternal toxicity, embryotoxicity or teratogenicity Peri-/Post-natal toxicity: No maternal, foetal or neonatal toxicity”
Safety pharmacology
ECG assessed in rhesus monkey combination study with chemotherapy; no significant findings
“A study of the administration of trastuzumab together with Taxol, Adriamycin, or Cytoxan/Adriamycin in rhesus monkeys did not elicit significant findings on parameters like mortality and clinical observations, body weights, electrocardiograms, clinical pathology including hematology, serum chemistry and urinalysis.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Herceptin don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey (EMA assessment report, p. 8)
NOAEL / key findings
Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey
“In all three studies there was a minimal toxic response, with the only noteworthy observations concerning injection-site trauma in the rhesus monkey.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies rare: 1/84 animals in repeat-dose studies
“This represents an incidence of 1/84 animals in repeated-dose studies in which antibodies to trastuzumab were detected.”
Biodistribution & persistence
TCR in monkey and human tissue showed no localisation to heart tissue
“Tissue cross reactivity studies with trastuzumab in monkey and human tissue did not reveal localisation to heart tissue.”
Modality-specific risk
Cardiotoxicity, enhanced in combination with anthracyclines such as doxorubicin
“Preclinical studies have been undertaken in an attempt to elucidate the mechanism for the enhanced cardiotoxicity observed in some clinical-trial patients receiving trastuzumab in combination with an anthracycline-based cytotoxic such as doxorubicin.”