Herceptin | Pharmacology Mentor

Generic Name

Herceptin

Mechanism

Herceptin (trastuzumab) is a humanized *interfering* monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor‑2 (HER2/neu).
• Receptor blockade: Occupation of HER2 prevents ligand‑independent dimerization and downstream signaling (PI3K/AKT and MAPK pathways).
• Antibody‑dependent cellular cytotoxicity (ADCC): Fc region engages NK cells, macrophages, and neutrophils to destroy the tumor cell.
• Inhibition of HER2 shedding: Reduces soluble HER2 ectodomain, dampening proliferative stimuli.
• Promotion of apoptosis: Trastuzumab triggers intracellular signaling that fosters programmed cell death in HER2‑overexpressing cancers.

The combination of direct oncogenic blockade and immune mediation is responsible for its efficacy in HER2‑positive breast and gastric cancers.

Pharmacokinetics

Parameter	Typical value	Notes
Absorption	Intravenous infusion	No oral absorption
Distribution	Vol. of distribution ≈ 23 L	Binds ~70 % to plasma proteins; limited tissue penetration
Half‑life	4–5 days (steady‑state ~6 days with multiple infusions)	Linear kinetics up to 8 mg/kg
Metabolism	Proteolytic cleavage of IgG backbone	Not hepatic or renal clearance
Elimination	Catabolism in reticuloendothelial system	Trough levels maintained with 6‑week intervals

Indications

Disease	Population	Regimen
HER2‑positive metastatic breast cancer	Adults & adolescents ≥12 y	8 mg/kg IV on day 1, then 6 mg/kg IV q3w
HER2‑positive early‑stage breast cancer (adjuvant)	Post‑surgery patients	2 mg/kg IV q3w for 1 year
HER2‑positive metastatic gastric/gastro‑oesophageal junction adenocarcinoma	Adults	8 mg/kg IV on day 1, then 6 mg/kg IV q3w
HER2‑positive breast cancer with trastuzumab‐combination adjuvant therapy	Adults	2 mg/kg IV q3w for 1 year (same as above)

*Contra‑indications*: Active uncontrolled heart failure, severe LVEF < 50 %.

Contraindications

Contraindicated in patients with known hypersensitivity to trastuzumab or murine proteins.
Warnings:
*Cardiotoxicity*: ~10–15 % develop LV dysfunction; higher with anthracyclines or higher cumulative doses.
*Infusion reactions*: often mild to moderate; grade 3‑4 reactions occur in <5 %.
*Premature labor*: Teratogenic; strict contraception required for up to 60 days postpartum.
Precautions: Avoid concurrent use with agents that also depress cardiac function; monitor LVEF before first infusion and at 3‑month intervals.

Dosing

Initial bolus: 8 mg/kg IV over 90 min (or 2 mg/kg for adjuvant).
Maintenance infusion: 6 mg/kg IV over 30 min every 3 weeks.
Premedication: Antihistamines (e.g., diphenhydramine) and acetaminophen reduce infusion reaction risk.
Route: Intravenous; infusion time may decrease with repeat cycles after tolerance.
Storage: Reconstituted solution stored at 2‑8 °C; do not refreeze.

Adverse Effects

Adverse Effect	Incidence	Management
Infusion reactions (fever, chills, rash)	10–15 % (most mild)	Premedicate, pause infusion, treat with antihistamines, vasopressors for severe cases
Cardiac dysfunction (decreased LVEF, CHF)	5–15 %	Baseline & serial echocardiograms; hold dose if EF 48 h symptoms
Hypersensitivity reactions	<1 %	Stop infusion, treat with corticosteroids and antihistamines
Pulmonary toxicity	<1 %	Monitor for dyspnea; discontinue if suspected

Monitoring

Cardiac:
Baseline & every 3 months: LVEF (echocardiography, MUGA).
Symptoms of heart failure (dyspnea, edema).
Infusion:
Vital signs during first 30 min; titrate infusion rate.
Laboratory:
CBC, BMP before each infusion (only if concomitant chemotherapy).
Serum cardiac troponin or BNP if cardiac symptoms arise.
Pregnancy:
Confirm pregnancy prior to initiation; due to teratogenicity.

Clinical Pearls

Synergy with Anthracyclines? Early trials showed increased cardiac risk; modern protocols avoid concurrent anthracyclines.
Trastuzumab‑chemo sequencing: Administer trastuzumab after a 1–2 week break from anthracyclines to mitigate cardiotoxicity.
Cardiac protection: Beta‑blockers and ACE inhibitors may pre‑emptively reduce trastuzumab‑related LV dysfunction in high‑risk patients.
Interpreting EGFR‑like effects: HER2 cross‑reactivity may lead to mild skin rash; differentiate from EGFR inhibitors.
Discontinuation: Dose interruption for ≥2 weeks or stoppage in case of symptomatic heart failure; restart per cardiology guideline upon EF recovery.
Pregnancy data: Animal studies show fetal malformations; restrict use to case‑by‑case, but first‑trimester exposure often leads to pregnancy loss.
Cardiac imaging: MUGA is more reproducible for serial LVEF assessment compared to echocardiography; use the same modality throughout treatment.