TIRZEPATIDE

Peptide Data Sheet for Pharmacists and Compounding Professionals

BASIC INFORMATION

Name: Tirzepatide
Class: Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist
Structure: 39-amino acid synthetic peptide
Molecular Weight: 4813.58 g/mol
Chemical Modifications:

  • C20 fatty diacid moiety attached to lysine at position 20
  • Amino acid substitutions to enhance stability and receptor binding

Available Forms:

  • FDA-approved injectable solution (Mounjaro®, Zepbound®)
  • Compounded formulations (subject to regulatory requirements)

REGULATORY STATUS

FDA Status

  • Mounjaro®: Approved for type 2 diabetes management (May 2022)
  • Zepbound®: Approved for chronic weight management (November 2023)

Compounding Considerations

  • Compounding must comply with USP <797> standards
  • Not eligible for compounding when FDA-approved versions are commercially available unless clinical need for modification is documented
  • Requires sterile compounding techniques

MECHANISM OF ACTION

Tirzepatide has a unique dual mechanism:

  1. GIP Receptor Activation:
    • Enhances glucose-dependent insulin secretion
    • Decreases glucagon secretion
    • Improves insulin sensitivity
  2. GLP-1 Receptor Activation:
    • Increases glucose-dependent insulin secretion
    • Decreases inappropriate glucagon secretion
    • Slows gastric emptying
    • Increases satiety and reduces food intake

The dual receptor activation provides enhanced glycemic control and weight loss compared to selective GLP-1 receptor agonists.

Mechanism of Action

PHARMACOKINETICS

| Parameter | Value | Notes | |———–|——-|——-| | Absorption | Subcutaneous: ~80% bioavailability | Peak plasma concentration: 8-72 hours | | Distribution | Volume of distribution: ~10.3 L | >99% plasma protein bound | | Metabolism | Proteolytic cleavage of peptide backbone | Resistant to DPP-4 degradation | | Elimination | Half-life: ~5 days (120 hours) | Primarily renal clearance |

CLINICAL APPLICATIONS

FDA-Approved Indications

  1. Type 2 Diabetes Management (Mounjaro®)
    • Improves glycemic control as adjunct to diet and exercise
    • Typical HbA1c reduction: 1.8-2.1% (10 mg dose)
    • Comparative efficacy: Superior to semaglutide 1 mg in head-to-head trials
  2. Chronic Weight Management (Zepbound®)
    • For adults with BMI ≥30 kg/m², or ≥27 kg/m² with weight-related comorbidity
    • Average weight loss: 15-20.9% of body weight over 72 weeks
    • Maintenance of weight loss with continued therapy

Off-Label/Investigational Uses

  • Non-alcoholic steatohepatitis (NASH)
  • Cardiovascular risk reduction
  • Obesity-related complications
  • Polycystic ovary syndrome (PCOS)

DOSING GUIDELINES

Type 2 Diabetes (Mounjaro®)

| Week | Dose | Administration | |——|——|—————-| | 1-4 | 2.5 mg | Once weekly, subcutaneous | | 5-8 | 5 mg | Once weekly, subcutaneous | | 9-12 | 7.5 mg | Once weekly, subcutaneous | | 13-16 | 10 mg | Once weekly, subcutaneous | | 17+ (if needed) | 12.5 mg | Once weekly, subcutaneous | | Maintenance (if needed) | 15 mg | Once weekly, subcutaneous |

Weight Management (Zepbound®)

| Week | Dose | Administration | |——|——|—————-| | 1-4 | 2.5 mg | Once weekly, subcutaneous | | 5-8 | 5 mg | Once weekly, subcutaneous | | 9-12 | 7.5 mg | Once weekly, subcutaneous | | 13-16 | 10 mg | Once weekly, subcutaneous | | 17+ (if needed) | 12.5 mg | Once weekly, subcutaneous | | Maintenance (if needed) | 15 mg | Once weekly, subcutaneous |

Dose Adjustments:

  • Dose escalation may be delayed based on tolerability
  • Temporary dose reduction may be considered for tolerability issues
  • Patients with renal impairment may require slower titration

ADMINISTRATION

Subcutaneous Injection

  • Administer in abdomen, thigh, or upper arm
  • Rotate injection sites
  • May be administered without regard to meals
  • Store refrigerated (2-8°C/36-46°F)
  • May be stored at room temperature (up to 30°C/86°F) for up to 21 days

SAFETY PROFILE

Contraindications

  • Personal or family history of medullary thyroid carcinoma
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
  • Hypersensitivity to tirzepatide or any excipients
  • Pregnancy (Zepbound®)

Warnings and Precautions

  • Boxed Warning: Risk of thyroid C-cell tumors
  • Pancreatitis
  • Diabetic retinopathy complications
  • Acute kidney injury
  • Hypoglycemia (when used with insulin or insulin secretagogues)
  • Acute gallbladder disease
  • Hypersensitivity reactions

Common Adverse Effects

| System | Adverse Effects | Approximate Incidence | |——–|—————-|————————| | Gastrointestinal | Nausea | 17-25% | | | Vomiting | 6-12% | | | Diarrhea | 13-17% | | | Abdominal pain | 6-10% | | | Constipation | 5-7% | | General | Fatigue | 5-7% | | | Injection site reactions | 1-3% | | Metabolic | Decreased appetite | 10-12% |

Drug Interactions

  • Delayed absorption of oral medications due to slowed gastric emptying
  • Increased risk of hypoglycemia when used with insulin or insulin secretagogues
  • Potential additive effects with other medications that cause hypoglycemia

SPECIAL POPULATIONS

Renal Impairment

  • No dose adjustment required for mild to moderate renal impairment
  • Limited experience in severe renal impairment (eGFR <30 mL/min/1.73m²)
  • Use caution and monitor renal function when initiating or escalating doses

Hepatic Impairment

  • No dose adjustment required for mild, moderate, or severe hepatic impairment
  • Limited clinical experience in severe hepatic impairment

Geriatric Patients

  • No dose adjustment required based on age
  • Greater sensitivity in some older individuals
  • Start at lower doses and titrate more slowly if needed

Pregnancy and Lactation

  • Pregnancy: Not recommended for use in pregnancy
  • Lactation: Unknown if excreted in human milk; use caution

PHARMACIST GUIDANCE

Compounding Considerations

  • Requires aseptic technique and sterile compounding environment
  • Stability affected by temperature, pH, and mechanical agitation
  • Incompatible with strongly acidic or basic solutions
  • Adhere to USP <797> standards for sterile compounding

Storage and Handling

  • Store in refrigerator (2-8°C/36-46°F)
  • Protect from light
  • Do not freeze
  • Discard if frozen
  • Stable at room temperature for up to 21 days

Patient Counseling Points

  1. Administration Technique
    • Proper subcutaneous injection technique
    • Importance of injection site rotation
    • Proper disposal of needles and syringes
  2. Gastrointestinal Side Effects
    • Typically transient and decrease over time
    • Small, frequent meals may help
    • Adequate hydration important
    • Contact healthcare provider if severe or persistent
  3. Hypoglycemia Risk
    • Signs and symptoms of hypoglycemia
    • Proper management of hypoglycemia
    • Importance of blood glucose monitoring
  4. Monitoring Parameters
    • Regular monitoring of blood glucose
    • Regular monitoring of weight
    • Regular monitoring of renal function
    • Regular monitoring of pancreatic enzymes if symptoms of pancreatitis
  5. When to Seek Medical Attention
    • Severe abdominal pain (potential pancreatitis)
    • Persistent vomiting or inability to maintain hydration
    • Signs of allergic reaction
    • Visual changes

MAXIMIZING THERAPEUTIC OUTCOMES

Optimizing Efficacy

  • Gradual dose titration minimizes GI side effects and improves tolerability
  • Combination with lifestyle modifications enhances weight loss and glycemic control
  • Patient education improves adherence and outcomes
  • Regular follow-up and monitoring optimizes dose and manages side effects

Managing Common Challenges

  • GI Side Effects: Slow titration, small frequent meals, adequate hydration
  • Injection Site Reactions: Proper technique, site rotation, room temperature injection
  • Adherence: Weekly dosing improves compliance compared to daily medications
  • Cost: Patient assistance programs, insurance prior authorizations

Comparative Efficacy

| Outcome | Tirzepatide | Semaglutide | Notes | |———|————-|————-|——-| | HbA1c Reduction | 1.8-2.1% | 1.0-1.8% | Head-to-head SURPASS-2 trial | | Weight Loss | 15-20.9% | 15-18% | Higher average weight loss with tirzepatide | | GI Side Effects | Similar profile | Similar profile | Comparable tolerability |

REFERENCES

  1. FDA. Mounjaro (tirzepatide) Prescribing Information.
  2. FDA. Zepbound (tirzepatide) Prescribing Information.
  3. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515.
  4. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216.
  5. Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021;12(1):143-157.