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Pamidronic acid | CAS No: 40391-99-9 | GMP-certified suppliers
A medication that treats moderate to severe hypercalcemia of malignancy, Paget’s disease of bone, and osteolytic bone lesions from breast cancer and multiple myeloma.
Therapeutic categories
Primary indications
- Pamidronate is indicated to treat moderate to severe hypercalcemia of malignancy, moderate to severe Paget's disease of bone, osteolytic bone metastases of breast cancer, and osteolytic lesions of multiple myeloma
Product Snapshot
- Pamidronic acid is available as a lyophilized powder or solution for injection, suitable for intravenous and parenteral administration
- It is primarily used for treating hypercalcemia of malignancy, Paget's disease of bone, osteolytic bone metastases in breast cancer, and osteolytic lesions in multiple myeloma
- The product is approved for use in key regulatory markets including the United States and Canada
Clinical Overview
Clinically, pamidronic acid is indicated for the treatment of moderate to severe hypercalcemia associated with malignancy, moderate to severe Paget’s disease of bone, osteolytic bone metastases from breast cancer, and osteolytic lesions due to multiple myeloma. Its mechanism of action involves selective uptake into bone tissue, where it binds hydroxyapatite crystals. During osteoclast-mediated bone resorption, local acidification releases pamidronic acid, which is internalized by osteoclasts via fluid-phase endocytosis. Within osteoclasts, pamidronic acid disrupts the formation of podosome structures essential for bone resorption, leading to osteoclast detachment and inhibited bone degradation.
At the molecular level, pamidronic acid inhibits key enzymes in the mevalonate pathway, including farnesyl diphosphate synthase, thereby reducing prenylation of small GTP-binding proteins such as Rap1. This disruption promotes apoptosis in hematopoietic tumor cells. Additionally, activation of caspases 3 and 9 contributes to apoptotic signaling.
Pharmacodynamically, pamidronic acid exhibits a wide therapeutic index and a prolonged duration of effect, allowing dosing intervals of three to four weeks for certain indications. Key safety considerations include risks of nephrotoxicity such as elevated blood urea nitrogen and renal tubular necrosis, warranting renal function monitoring during therapy.
From an ADME perspective, pamidronic acid demonstrates high affinity for bone tissue with limited systemic metabolism. Renal excretion is the primary elimination pathway.
Pamidronic acid is recognized within various drug categories, including antineoplastic agents, bone density conservation agents, and nephrotoxic agents. It remains relevant in oncologic and metabolic bone disease contexts, although newer third-generation bisphosphonates have gained popularity in recent years.
In sourcing pamidronic acid API, attention should be given to supplier compliance with pharmacopeial standards and regulatory requirements, ensuring consistent purity, stability, and absence of contaminants. Manufacturing processes should adhere to Good Manufacturing Practice (GMP) to support quality assurance for pharmaceutical formulations.
Identification & chemistry
| Generic name | Pamidronic acid |
|---|---|
| Molecule type | Small molecule |
| CAS | 40391-99-9 |
| UNII | OYY3447OMC |
| DrugBank ID | DB00282 |
Pharmacology
| Summary | Pamidronate is a nitrogen-containing bisphosphonate that binds to bone mineral and inhibits osteoclast-mediated bone resorption by disrupting osteoclast attachment and inducing apoptosis. It targets enzymes in the mevalonate pathway, such as farnesyl diphosphate synthase, leading to impaired prenylation of GTP-binding proteins and activation of apoptotic caspases. These mechanisms contribute to its therapeutic use in conditions characterized by excessive bone degradation. |
|---|---|
| Mechanism of action | Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as pamidronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. pamidronate also activated caspases 3 and 9 which further contribute to apoptosis. |
| Pharmacodynamics | Pamidronic acid is a second generation, nitrogen containing bisphosphonate that inhibits osteoclast mediated bone loss It has a wide therapeutic index and a long duration of action as it can be given every 3-4 weeks for certain indications. Patients should be counselled regarding the risk of elevated blood urea nitrogen, renal tubular necrosis, and nephrotoxicity. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Farnesyl pyrophosphate synthase | Humans | inhibitor |
| Hydroxylapatite | Humans | antagonist |
| Geranylgeranyl pyrophosphate synthase | Humans | inhibitor |
ADME / PK
| Absorption | In patients with a creatinine clearance >90mL/min, a 90mg intravenous dose reached a C<sub>max</sub> of 1.92±1.08µg/mL, with a T<sub>max</sub> of 4h, and an AUC of 10.2±6.95µg\*h/mL. In patients with a creatinine clearance 61-90mL/min, a 90mg intravenous dose reached a C<sub>max</sub> of 1.86±0.50µg/mL, with a T<sub>max</sub> of 4h, and an AUC of 10.7—3.91µg\*h/mL.[A203264 In patients with a creatinine clearance 30-60mL/min, a 90mg intravenous dose reached a C<sub>max</sub> of 1.84±0.58µg/mL, with a T<sub>max</sub> of 4h, and an AUC of 10.1±3.38µg\*h/mL. In patients with a creatinine clearance <30mL/min, a 90mg intravenous dose reached a C<sub>max</sub> of 1.93±0.53µg/mL, with a T<sub>max</sub> of 4h, and an AUC of 34.0±8.37µg\*h/mL. |
|---|---|
| Half-life | The mean elimination half life of pamidronate is 28±7 hours. |
| Protein binding | Pamidronate is approximately 54% protein bound in serum. |
| Metabolism | Pamidronate is not metabolized _in vivo_. |
| Route of elimination | Pamidronate is exclusively eliminated in the urine. By 120 hours after administration, 46±16% of the dose has been eliminated in the urine. |
| Clearance | The mean total clearance of pamidronate is 107±50mL/min and the mean renal clearance is 49±28mL/min. |
Formulation & handling
- Pamidronic acid is formulated primarily for intravenous administration as a lyophilized powder or solution due to its high water solubility and low logP.
- As a small molecule bisphosphonate, it does not exhibit peptide or biologic characteristics but requires sterile handling typical of parenteral APIs.
- Stability considerations include protection from moisture and appropriate reconstitution prior to administration to maintain potency and ensure safety.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is approaching patent expiration in key markets including the US and Canada, indicating a transition toward increased generic competition. This shift reflects advancing market maturity and potential changes in product accessibility. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | Pamidronic acid is produced by multiple manufacturers, including originator companies such as Novartis Pharmaceuticals Corp, alongside various generic manufacturers. Branded products, primarily marketed under the name Aredia, have a presence mainly in the US and Canadian markets. Patent expiry has led to established generic competition, as evidenced by numerous generic manufacturers and packagers active in these regions. |
|---|
Safety
| Toxicity | Patients experiencing and overdose may present with hypocalcemia, fever, hypotension, and taste perversion. Overdose can be managed by symptomatic and supportive treatment which may include the administration of steroids and intravenous calcium. |
|---|
- Exposure may cause systemic toxicity including hypocalcemia, fever, and hypotension
- Handle with appropriate protective equipment to prevent accidental ingestion or dermal exposure
- In case of overdose, supportive measures including administration of steroids and intravenous calcium are indicated
Pamidronate is a type of Bisphosphonates
Bisphosphonates are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) widely used in the treatment of various bone-related conditions. These compounds play a crucial role in inhibiting bone resorption, making them particularly effective in managing diseases such as osteoporosis, Paget's disease, and bone metastasis associated with cancer.
The mechanism of action of bisphosphonates involves their binding to hydroxyapatite crystals in bone, leading to the suppression of osteoclast activity. By inhibiting the breakdown of bone tissue, these APIs help to maintain bone density and strength, thereby reducing the risk of fractures and improving overall bone health.
One of the key advantages of bisphosphonates is their high affinity for bone tissue, which allows for targeted treatment. They are administered orally or intravenously, depending on the specific formulation and indication. Commonly prescribed bisphosphonates include alendronate, ibandronate, and zoledronic acid, among others.
Bisphosphonates are generally well-tolerated, although some potential side effects, such as gastrointestinal disturbances or musculoskeletal pain, may occur. These APIs are metabolized in the liver and excreted through the kidneys.
Due to their effectiveness and widespread clinical use, bisphosphonates have gained significant attention in the pharmaceutical industry. Continuous research and development efforts are focused on improving their therapeutic profiles, including enhancing potency and reducing side effects.
In summary, bisphosphonates are a critical subcategory of pharmaceutical APIs employed in the management of bone-related disorders. Their targeted action on bone tissue and ability to inhibit bone resorption make them indispensable in the treatment of conditions like osteoporosis and bone metastasis. Ongoing advancements in this field are expected to further optimize their therapeutic benefits in the future.
Pamidronate (Bisphosphonates), classified under Metabolic Bone Disease Agents
Metabolic Bone Disease Agents are a category of pharmaceutical active pharmaceutical ingredients (APIs) that are specifically designed to treat and manage conditions related to the bones and their metabolism. These agents play a crucial role in the treatment of various metabolic bone diseases, including osteoporosis, Paget's disease, and rickets.
The primary function of Metabolic Bone Disease Agents is to regulate bone remodeling and maintain bone health. They achieve this by targeting specific pathways involved in bone metabolism, such as osteoclast and osteoblast activity, calcium regulation, and vitamin D metabolism.
These APIs are commonly used in the development of medications, including oral tablets, injectables, and topical formulations, for the effective treatment of metabolic bone diseases. They are carefully formulated to optimize their pharmacokinetic and pharmacodynamic properties, ensuring maximum efficacy and minimal side effects.
Metabolic Bone Disease Agents encompass a range of substances, including bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and vitamin D analogs. These APIs act through different mechanisms to address specific aspects of bone health, such as inhibiting bone resorption, promoting bone formation, or regulating calcium levels.
In conclusion, Metabolic Bone Disease Agents are a vital category of pharmaceutical APIs used in the development of medications for the treatment and management of various metabolic bone diseases. These agents target specific pathways involved in bone metabolism to regulate bone remodeling, enhance bone health, and alleviate the symptoms associated with these conditions.
Pamidronate API manufacturers & distributors
Compare qualified Pamidronate API suppliers worldwide. We currently have 1 companies offering Pamidronate API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Hospira Boulder | Producer | United States | United States | CoA, USDMF | 5 products |
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