Pembrolizumab

Usage

Pembrolizumab is prescribed for the treatment of various cancers, including:

• Melanoma (unresectable or metastatic)
• Non-small cell lung cancer (NSCLC)
• Head and neck squamous cell carcinoma (HNSCC)
• Classical Hodgkin lymphoma (cHL)
• Primary mediastinal large B-cell lymphoma (PMBCL)
• Urothelial carcinoma
• Renal cell carcinoma (RCC)
• Cervical cancer
• Merkel cell carcinoma (MCC)
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors (adults and children)
• Tumor mutational burden-high (TMB-H) solid tumors (adults and children)
• Triple-negative breast cancer (TNBC)

Pharmacological Classification: Pembrolizumab is classified as an antineoplastic agent, specifically an immune checkpoint inhibitor. It is a humanized monoclonal antibody.

Mechanism of Action: Pembrolizumab blocks the interaction between programmed death-1 (PD-1) receptor and its ligands, PD-L1 and PD-L2. This blockade prevents the inhibition of T-cell activity, enhancing the immune system’s ability to recognize and attack cancer cells.

Alternate Names

International Nonproprietary Name (INN): Pembrolizumab

Brand Name: Keytruda

How It Works

Pharmacodynamics: Pembrolizumab binds to the PD-1 receptor on T-cells, inhibiting the interaction with its ligands, PD-L1 and PD-L2. This inhibition releases the “brakes” on the immune system, increasing T-cell activation and proliferation and enhancing anti-tumor immune responses.

Pharmacokinetics:

• Absorption: Administered intravenously.
• Distribution: Distributed into extracellular fluid; does not bind extensively to plasma proteins. Reaches steady-state concentration by 16 weeks with every-3-weeks dosing.
• Metabolism: Catabolized through non-specific pathways.
• Elimination: Primarily via non-specific catabolism, not through hepatic or renal routes. Terminal half-life is approximately 22 days.

Mode of Action: Pembrolizumab’s mode of action involves receptor binding. By binding to the PD-1 receptor, it prevents the binding of its ligands, which normally suppress T-cell activation. This leads to increased T-cell activity against tumor cells. No CYP enzyme interactions are known.

Elimination Pathways: Pembrolizumab is eliminated through non-specific protein catabolism rather than hepatic or renal clearance.

Dosage

Pembrolizumab is administered via intravenous infusion over 30 minutes. Dosages are based on body weight or fixed doses, with variations depending on the specific cancer type and treatment regimen. Two common dosing regimens are 200 mg every 3 weeks or 400 mg every 6 weeks.

Standard Dosage

Adults: 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or for a specified duration depending on the cancer being treated.

Children (for approved indications): 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.

Special Cases:

• Elderly Patients: No dose adjustment is typically necessary.
• Patients with Renal Impairment: No dose adjustment is typically necessary.
• Patients with Hepatic Dysfunction: No dose adjustment is typically necessary.
• Patients with Comorbid Conditions: Dose modifications may be needed depending on the specific comorbidity and its impact on drug tolerance.

Clinical Use Cases

Pembrolizumab is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, or emergency situations (e.g., cardiac arrest) like other drug classes (e.g., anesthetics, vasopressors). It is used for cancer treatment. Its use in the intensive care unit (ICU) would be related to managing side effects associated with the treatment.

Dosage Adjustments

Dose interruptions or discontinuation may be required for managing immune-related adverse events. No specific dose reductions based on organ dysfunction or metabolic disorders are routinely recommended.

Side Effects

Common Side Effects: Fatigue, diarrhea, rash, pruritus, nausea, vomiting, musculoskeletal pain, decreased appetite, cough, dyspnea, constipation.

Rare but Serious Side Effects: Pneumonitis, colitis, hepatitis, nephritis, endocrinopathies (thyroid disorders, type 1 diabetes, hypophysitis), severe skin reactions, neurological complications, infusion reactions.

Long-Term Effects: Long-term immune-related adverse events can occur, sometimes even after treatment discontinuation, and require ongoing monitoring.

Adverse Drug Reactions (ADR): Any immune-related adverse event reaching Grade 3 or 4 severity should prompt immediate evaluation and management.

Contraindications

• Hypersensitivity to pembrolizumab or any component of the formulation.

Drug Interactions

• Systemic corticosteroids or immunosuppressants: Use before starting pembrolizumab should be avoided. These can be used after starting pembrolizumab for the management of immune-related adverse reactions.
• Other clinically significant drug interactions: No metabolic drug interactions are expected as pembrolizumab is cleared via catabolism. Always consult a drug interaction checker for the most up-to-date and comprehensive information before co-prescribing medications with pembrolizumab.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Based on its mechanism of action, pembrolizumab can cause fetal harm. It should be avoided during pregnancy unless the benefits clearly outweigh the risks.
• Breastfeeding: It is unknown if pembrolizumab is present in human milk. Breastfeeding is not recommended during treatment and for 4 months after the last dose.

Drug Profile Summary

• Mechanism of Action: PD-1 inhibitor, enhancing T-cell activity.
• Side Effects: Fatigue, diarrhea, rash, pruritus; serious immune-related adverse events are possible.
• Contraindications: Hypersensitivity to pembrolizumab.
• Drug Interactions: Avoid systemic corticosteroids or immunosuppressants before starting therapy.
• Pregnancy & Breastfeeding: Contraindicated or not recommended.
• Dosage: 200 mg every 3 weeks or 400 mg every 6 weeks (adults); 2 mg/kg every 3 weeks (children, specific indications).
• Monitoring Parameters: Monitor for immune-related adverse events (e.g., pneumonitis, colitis, hepatitis, endocrinopathies), complete blood counts, and other laboratory tests as clinically indicated.

Popular Combinations

Pembrolizumab can be combined with chemotherapy (e.g., platinum-based chemotherapy for NSCLC, chemotherapy for TNBC), targeted therapies (e.g., axitinib for RCC, lenvatinib for RCC and endometrial carcinoma), or other immunotherapies. The specific combination depends on the cancer type and treatment goals.

Precautions

• General Precautions: Assess for active infections, autoimmune diseases, or history of severe immune-related adverse reactions before initiating treatment.
• Specific Populations:
  • Pregnant Women: Avoid use unless potential benefits outweigh the risks.
  • Breastfeeding Mothers: Not recommended.
  • Children & Elderly: Monitor closely for adverse effects.
• Lifestyle Considerations: No specific restrictions on alcohol, smoking, or diet are routinely necessary, but advise patients to maintain a healthy lifestyle. Driving restrictions may be needed depending on individual side effects experienced.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Pembrolizumab?

A: The standard adult dosage is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks. For children (specific indications), the dosage is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks. Dosage adjustments may be necessary based on the specific disease and patient tolerance.

Q2: What are the most common side effects of Pembrolizumab?

A: The most frequently reported side effects include fatigue, diarrhea, rash, itching, nausea, vomiting, musculoskeletal pain, decreased appetite, cough, and shortness of breath.

Q3: What are the serious side effects to watch out for with Pembrolizumab?

A: Rare but potentially life-threatening immune-related adverse reactions can occur, such as pneumonitis, colitis, hepatitis, nephritis, and endocrinopathies. Patients should be closely monitored for these complications.

Q4: Can Pembrolizumab be used during pregnancy?

A: Pembrolizumab can cause fetal harm and should be avoided during pregnancy unless the potential benefits outweigh the risks to the fetus.

Q5: Is it safe to breastfeed while taking Pembrolizumab?

A: It is unknown if pembrolizumab passes into breast milk. Due to the potential for adverse effects in the infant, breastfeeding is not recommended during treatment and for 4 months after the last dose.

Q6: How is Pembrolizumab administered?

A: Pembrolizumab is given as an intravenous infusion over 30 minutes in a hospital or clinical setting under the supervision of a healthcare professional.

Q7: Are there any contraindications for Pembrolizumab?

A: A known hypersensitivity to pembrolizumab or any of its components is a contraindication to its use.

Q8: Does Pembrolizumab interact with other medications?

A: The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided as they can interfere with its activity. However, these agents can be used after starting pembrolizumab to manage immune-related adverse reactions. Consult a drug interaction checker for a comprehensive review of potential interactions.

Q9: How long is a typical course of treatment with Pembrolizumab?

A: The duration of treatment varies depending on the specific type of cancer, the patient’s response to treatment, and the development of any unacceptable side effects. Treatment may continue for up to 24 months or until disease progression or unacceptable toxicity, as determined by the treating physician.