Trastuzumab

Introduction/Overview

Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain of the human epidermal growth factor receptor 2 (HER2). It has become a cornerstone of therapy for HER2-positive breast cancer and other malignancies expressing HER2. The clinical impact of trastuzumab is substantial, with significant improvements in overall survival and disease-free survival when combined with chemotherapy or used as monotherapy. Understanding its pharmacologic profile is essential for clinicians, pharmacists, and researchers involved in oncology care.

Learning objectives for this chapter include:

• Identify the classification and chemical characteristics of trastuzumab.
• Explain the pharmacodynamic mechanisms that underlie its antitumor activity.
• Describe the pharmacokinetic parameters and dosing strategies employed in clinical practice.
• Outline approved and off‑label therapeutic indications, including dosing regimens.
• Recognize common and serious adverse effects, as well as drug interactions and special population considerations.

Classification

Drug Classes and Categories

Trastuzumab belongs to the class of therapeutic monoclonal antibodies (mAbs). Within this category, it is further classified as a humanized IgG1 kappa antibody. It is typically administered intravenously and is formulated as an aqueous solution suitable for infusion.

Chemical Classification

As a recombinant protein, trastuzumab consists of 1,065 amino acids, with a molecular weight of approximately 149 kDa. The variable regions of the heavy and light chains confer specificity for HER2, while the constant region mediates effector functions such as antibody-dependent cellular cytotoxicity (ADCC). The glycosylation pattern on the Fc domain is critical for its pharmacologic activity and is maintained during manufacturing.

Mechanism of Action

Pharmacodynamics

Trastuzumab binds with high affinity to subdomain IV of the HER2 extracellular domain. This interaction prevents ligand-independent dimerization of HER2 with other EGFR family members and blocks downstream signaling pathways. By inhibiting the PI3K/AKT and MAPK cascades, trastuzumab decreases proliferation and increases apoptosis in HER2-overexpressing cells.

Receptor Interactions

Binding of trastuzumab to HER2 induces receptor internalization and degradation. Additionally, the antibody sterically hinders the shedding of HER2 extracellular fragments, thereby reducing circulating HER2 levels that may contribute to tumor growth. The blocking of HER2 also disrupts the formation of HER2/HER3 heterodimers, which are particularly potent in promoting oncogenic signaling.

Molecular/Cellular Mechanisms

Beyond receptor blockade, trastuzumab activates innate immune effector mechanisms. Engagement of the Fcγ receptor on natural killer (NK) cells triggers ADCC, resulting in targeted cell lysis. The antibody also induces complement-dependent cytotoxicity (CDC) through classical pathway activation, although this mechanism contributes less to clinical efficacy compared with ADCC. Finally, trastuzumab can sensitize tumor cells to chemotherapeutic agents by modulating drug transporters and apoptotic thresholds.

Pharmacokinetics

Absorption

Trastuzumab is administered intravenously; thus, absorption is immediate. No oral absorption occurs due to protein degradation in the gastrointestinal tract.

Distribution

After infusion, trastuzumab distributes primarily within the vascular and interstitial compartments. The apparent volume of distribution (V_d) is approximately 3.0 L/kg. Distribution to tumor tissue is facilitated by vascular permeability and the presence of HER2 receptors. Interindividual variability in V_d can be influenced by body weight, albumin levels, and disease state.

Metabolism

Metabolism of monoclonal antibodies occurs via proteolytic catabolism, yielding small peptides and amino acids. Unlike small-molecule drugs, trastuzumab is not subject to hepatic cytochrome P450 metabolism. Clearance pathways involve reticuloendothelial system processing and lysosomal degradation within cells that bind the antibody.

Excretion

Renal excretion of intact trastuzumab is negligible. The antibody is eliminated largely through target-mediated drug disposition (TMDD) and non-specific catabolic pathways. Clearance rates may be reduced in patients with high tumor burden due to increased target-mediated uptake.

Half‑Life and Dosing Considerations

The terminal half-life (t_1/2) of trastuzumab is approximately 4–5 weeks. The recommended loading dose is 8 mg/kg, followed by 6 mg/kg every 3 weeks for 12 cycles in metastatic breast cancer, or 4 mg/kg every 2 weeks in adjuvant therapy. Dosing intervals may be extended to every 6 weeks when combined with certain chemotherapeutic agents or in the adjuvant setting, provided serum trough concentrations remain above therapeutic thresholds. Accumulation occurs with repeated dosing; thus, monitoring of serum levels is not routinely required but may be considered in atypical response or toxicity scenarios.

Therapeutic Uses/Clinical Applications

Approved Indications

Trastuzumab is approved for HER2-positive metastatic breast cancer as monotherapy or in combination with taxanes, anthracyclines, or capecitabine. In the adjuvant setting, it is indicated for early-stage HER2-positive breast cancer following anthracycline- and taxane-based chemotherapy. Trastuzumab has also been approved for HER2-positive gastric or gastroesophageal junction adenocarcinoma in combination with chemotherapy. Moreover, the combination of trastuzumab with pertuzumab is approved for metastatic HER2-positive breast cancer.

Off‑Label Uses

Clinical practice occasionally employs trastuzumab for HER2-positive metastatic colorectal cancer, ovarian cancer, and certain breast cancer subtypes expressing low HER2 levels. While evidence is limited, these uses may be considered in refractory cases or within clinical trials. Additionally, trastuzumab has been investigated in HER2-expressing brain metastases, though blood–brain barrier penetration remains suboptimal.

Adverse Effects

Common Side Effects

• Infusion reactions, typically mild to moderate, occurring during the first infusion. Symptoms may include fever, chills, headache, and hypotension.
• Cardiotoxicity manifested as decreased left ventricular ejection fraction (LVEF) or heart failure, particularly when combined with anthracyclines. Monitoring of LVEF via echocardiography or MUGA scans is recommended.
• Hematologic events such as neutropenia, leukopenia, and thrombocytopenia, especially when combined with cytotoxic agents.
• Gastrointestinal disturbances, including nausea, vomiting, and diarrhea, which are generally mild.
• Skin rash and alopecia, though less frequent than with other biologics.

Serious or Rare Adverse Reactions

• Severe cardiotoxicity leading to congestive heart failure, potentially irreversible.
• Hypersensitivity reactions requiring discontinuation of therapy.
• Infusion-associated anaphylaxis, particularly in patients with prior exposure to monoclonal antibodies.
• Rare cases of interstitial lung disease and pulmonary fibrosis.

Black Box Warnings

Cardiac dysfunction is a principal concern. The drug product information includes a black box warning regarding the risk of heart failure, especially when used concomitantly with anthracyclines or in patients with pre-existing cardiac disease. LVEF monitoring before, during, and after therapy is mandated. Additionally, a warning regarding the risk of neonatal heart failure exists when administered during the third trimester, necessitating caution or alternative therapies.

Drug Interactions

Major Drug–Drug Interactions

• Anthracyclines (e.g., doxorubicin, epirubicin): additive cardiotoxicity; co-administration requires careful cardiac monitoring.
• Taxanes (paclitaxel, docetaxel): potential for increased neuropathy; no pharmacokinetic interaction but overlapping toxicity profiles.
• Tyrosine kinase inhibitors (e.g., lapatinib, neratinib): possible additive HER2 blockade; clinical evidence suggests enhanced efficacy but increased toxicity.
• Immunosuppressants (e.g., cyclosporine, tacrolimus): may affect immune-mediated clearance of the antibody; dose adjustments are rarely required but should be monitored.

Contraindications

Patients with known hypersensitivity to trastuzumab or any component of the formulation, including polysorbate 80, are contraindicated. Additionally, patients with significant pre-existing cardiac dysfunction (LVEF <55%) or uncontrolled hypertension should avoid therapy unless benefits outweigh risks.

Special Considerations

Use in Pregnancy and Lactation

Trastuzumab is classified as category D for pregnancy. Animal studies demonstrate fetal toxicity, particularly cardiotoxicity, when exposure occurs during the second and third trimesters. Consequently, it is contraindicated in pregnancy. Breastfeeding is discouraged due to the potential for systemic exposure through milk; patients are advised to discontinue lactation during treatment.

Pediatric Considerations

Limited data exist for pediatric use. Off‑label administration may occur in HER2-positive pediatric tumors or for investigational purposes. Dose adjustments are typically weight-based, and close monitoring for cardiotoxicity is essential. Pediatric pharmacokinetics suggest similar clearance rates to adults, but variability remains high.

Geriatric Considerations

Older adults may exhibit reduced cardiac reserve and comorbidities that increase susceptibility to cardiotoxicity. Baseline cardiac evaluation and periodic LVEF assessments remain imperative. Pharmacokinetic parameters are largely unchanged in the elderly, yet dose adjustments may be warranted based on renal function and nutritional status.

Renal and Hepatic Impairment

Renal dysfunction does not significantly alter trastuzumab clearance, given its predominant catabolic elimination. Hepatic impairment has minimal impact; however, liver disease may influence overall patient tolerance to therapy and should prompt vigilant monitoring for hepatic enzymes and bilirubin levels.

Summary/Key Points

• Trastuzumab is a humanized IgG1 monoclonal antibody targeting HER2, used primarily in HER2-positive breast and gastric cancers.
• Its mechanism involves receptor blockade, inhibition of downstream signaling, and activation of ADCC.
• The drug follows a biexponential decay with a terminal half-life of ≈4–5 weeks; dosing is weight-based and typically administered every 3 weeks.
• Cardiotoxicity remains the most significant adverse effect; routine LVEF monitoring is recommended.
• Infusion reactions are common but manageable with premedication and slowed infusion rates.
• Concomitant use with anthracyclines necessitates heightened cardiac surveillance due to additive toxicity.
• Pregnancy and lactation are contraindicated; use in pediatric and geriatric populations requires careful monitoring for cardiac and general tolerability.
• Off-label applications exist but should be considered within clinical trials or when standard therapies fail.
• Drug interactions primarily involve additive toxicities rather than pharmacokinetic alterations.

Clinical practitioners should integrate pharmacodynamic knowledge, patient-specific factors, and vigilant monitoring to optimize trastuzumab therapy outcomes while minimizing adverse events.

References

1. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
2. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
3. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
8. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.