Recombinant Human parathyroid hormone (rhPTH(1-84))

Usage

• Recombinant human parathyroid hormone (rhPTH(1-84)) is prescribed as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism who are inadequately controlled with conventional therapy alone. It is particularly beneficial for patients who experience frequent episodes of hypo- or hypercalcemia despite standard treatments. It is important to note that due to the potential risk of osteosarcoma, rhPTH(1-84) is recommended only when conventional therapy is insufficient.
• Pharmacological Classification: Hormone, specifically a parathyroid hormone analog.
• Mechanism of Action: rhPTH(1-84) mimics the action of endogenous parathyroid hormone (PTH). It increases serum calcium levels by:
  • Increasing calcium reabsorption in the kidneys.
  • Increasing calcium absorption from the intestines (indirectly by stimulating the production of 1,25-dihydroxyvitamin D).
  • Stimulating bone formation through direct effects on bone-forming cells (osteoblasts), while also increasing bone resorption. The net effect on bone with intermittent dosing is bone formation.

Alternate Names

• rhPTH(1-84)
• Recombinant human parathyroid hormone 1-84
• Brand Name: Natpara, Preotact

How It Works

• Pharmacodynamics: rhPTH(1-84) binds to PTH/PTHrP receptors, primarily in bone and kidney, initiating signaling cascades that lead to increased serum calcium and decreased serum phosphate. Intermittent administration of rhPTH(1-84) stimulates bone formation and increases bone mineral density, while continuous exposure can lead to excessive bone resorption.

• Pharmacokinetics:

  • Absorption: Rapidly absorbed after subcutaneous injection, with peak plasma concentrations occurring within 5-30 minutes, followed by a second, smaller peak at 1-2 hours. Note: does not perfectly mimic the body’s natural PTH release pattern.
  • Metabolism: Primarily hepatic, with a smaller role played by the kidneys. Cleaved by cathepsins in the liver.
  • Elimination: Primarily renal and hepatic. C-terminal fragments cleared by glomerular filtration.
  • Half-life: Approximately 3 hours.

• Mode of Action: Binds to and activates PTH/PTHrP receptors, G protein-coupled receptors that primarily signal through the cAMP/PKA and PLC/PKC pathways.

• Receptor Binding: PTH1 receptor (PTH/PTHrP receptor).

• Elimination Pathways: Predominantly hepatic metabolism and renal excretion.

Dosage

Standard Dosage

Adults:

• Initial: 50 mcg subcutaneously once daily, administered in the thigh (alternate thighs daily).
• Titration: May increase by 25 mcg increments every 4 weeks, not to exceed 100 mcg/day, if serum calcium cannot be maintained above 8 mg/dL without active vitamin D and/or calcium supplementation. Conversely, the dose can be lowered to 25 mcg/day if calcium levels are consistently above 9 mg/dL after vitamin D has been discontinued and calcium supplements minimized.
• Maintenance: The lowest dose that maintains serum calcium (albumin-corrected) within the lower half of the normal range (8-9 mg/dL) without active vitamin D and with minimal calcium supplementation.

Children:

• Safety and efficacy not established in patients under 18 years old. No data are available.

Special Cases:

• Elderly Patients: Start with a lower initial dose (25 mcg daily) and titrate cautiously.
• Patients with Renal Impairment: No dose adjustment for mild to moderate impairment. Data not available for severe renal impairment (CrCl <30 mL/min), end-stage renal disease (ESRD), or dialysis patients.
• Patients with Hepatic Dysfunction: No dose adjustment for mild to moderate impairment. Data not available for severe hepatic impairment.
• Patients with Comorbid Conditions: Close monitoring of serum calcium is advised in patients with concomitant conditions such as hypercalciuria and urolithiasis. Monitor for signs and symptoms of digoxin toxicity if taking cardiac glycosides.

Clinical Use Cases

rhPTH(1-84) is specifically indicated for chronic hypoparathyroidism. It is not approved for use in acute settings such as those listed below:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations

Dosage Adjustments

• Dose adjustments should be based on serum calcium (albumin-corrected) and 24-hour urinary calcium excretion.

Side Effects

Common Side Effects:

• Hypocalcemia
• Muscle spasms
• Paresthesia
• Nausea
• Headache
• Sinusitis
• Injection site reactions

Rare but Serious Side Effects:

• Osteosarcoma (Black Box Warning)
• Hypercalcemia
• Renal impairment (in patients with pre-existing kidney disease)

Long-Term Effects:

• Potential for osteosarcoma with prolonged use.
• Possible changes in bone density distribution (increase in lumbar spine, variable effects on other sites).

Adverse Drug Reactions (ADR):

• Severe hypocalcemia or hypercalcemia requiring hospitalization.

Contraindications

• Absolute:

  • Hypersensitivity to rhPTH(1-84) or any of its components.
  • Pre-existing osteosarcoma or skeletal malignancies.
  • Paget’s disease of bone.
  • Unexplained elevations of alkaline phosphatase.
  • Open epiphyses (in children).
  • Hereditary disorders predisposing to osteosarcoma.
  • History of skeletal radiation therapy.

• Relative: Urolithiasis, hypercalciuria.

Drug Interactions

• Alendronate (and other bisphosphonates): Concomitant use is not recommended, as it reduces the calcium-sparing effect of rhPTH(1-84).
• Digoxin (Cardiac Glycosides): Increases the risk of digoxin toxicity if hypercalcemia develops. Careful monitoring required.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C. Use only if the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: It is unknown if rhPTH(1-84) is excreted in human milk. Exercise caution if administering to a nursing woman.

Drug Profile Summary

• Mechanism of Action: Mimics endogenous PTH to increase serum calcium levels by acting on bone and kidney.
• Side Effects: Hypocalcemia, muscle spasms, paresthesia, nausea, osteosarcoma (rare but serious).
• Contraindications: Osteosarcoma, Paget’s disease of bone, open epiphyses, previous skeletal radiation therapy.
• Drug Interactions: Alendronate, digoxin.
• Pregnancy & Breastfeeding: Category C; unknown if excreted in human milk.
• Dosage: Initial 50 mcg SC daily, titrated to effect; maximum 100 mcg daily.
• Monitoring Parameters: Serum calcium (albumin-corrected), 24-hour urinary calcium, serum phosphorus, creatinine, alkaline phosphatase, bone mineral density.

Popular Combinations

• Calcium and vitamin D supplements are often used concurrently with rhPTH(1-84), although the doses of these supplements should be adjusted when initiating rhPTH(1-84).

Precautions

• General Precautions: Monitor serum calcium closely, especially during initiation and titration. Monitor for signs of osteosarcoma. Ensure adequate vitamin D levels before starting therapy. Evaluate renal function prior to and during therapy.
• Specific Populations:
  • Pregnant Women: Use with caution; weigh risks and benefits.
  • Breastfeeding Mothers: Unknown if excreted in human milk; use with caution.
  • Children & Elderly: Safety and efficacy not established in children. Start with a lower dose in the elderly.
• Lifestyle Considerations: Counseling on diet and calcium intake is important.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for rhPTH(1-84)?

A: The initial dose is 50 mcg subcutaneously once daily. The dose is titrated based on the patient’s serum calcium and urinary calcium levels, up to a maximum of 100 mcg daily.

Q2: What are the most serious side effects of rhPTH(1-84)?

A: The most serious side effect is osteosarcoma. Other serious side effects include severe hypocalcemia and hypercalcemia.

Q3: Can rhPTH(1-84) be used during pregnancy?

A: It is a Pregnancy Category C drug, meaning that it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Q4: How is rhPTH(1-84) administered?

A: rhPTH(1-84) is administered as a subcutaneous injection once daily in the thigh. Patients can be trained to self-administer the injections.

Q5: What should be monitored during rhPTH(1-84) therapy?

A: Serum calcium (albumin-corrected), 24-hour urinary calcium, serum phosphorus, creatinine, and alkaline phosphatase should be monitored regularly. Bone mineral density should also be assessed periodically.

Q6: What is the mechanism of action of rhPTH(1-84)?

A: rhPTH(1-84) mimics the effects of endogenous parathyroid hormone by increasing calcium reabsorption in the kidneys, increasing calcium absorption from the gut, and stimulating bone formation and resorption. With intermittent dosing, the predominant effect on bone is formation.

Q7: Who should not take rhPTH(1-84)?

A: Patients with a history of osteosarcoma, Paget’s disease of bone, open epiphyses, or prior skeletal radiation should not take rhPTH(1-84).

Q8: What are the signs and symptoms of hypocalcemia?

A: Symptoms can include muscle cramps or spasms, numbness and tingling around the mouth or in the extremities, seizures, and cardiac arrhythmias.

Q9: What are the signs and symptoms of hypercalcemia?

A: Symptoms can include nausea, vomiting, constipation, abdominal pain, muscle weakness, confusion, and increased thirst and urination.

Q10: What should I do if my patient misses a dose of rhPTH(1-84)?

A: They should administer the missed dose as soon as possible. If they experience symptoms of hypocalcemia, they should take supplemental calcium.

Please note that this information is current as of February 17, 2025, and is subject to change as new data emerge.