nedosiran

Action and Spectrum

Actions and spectrum: 

Action: nedosiran acts by targeting and inhibiting a specific enzyme called lactate dehydrogenase A (LDHA). LDHA is involved in the glyoxylate pathway, which plays a critical role in the oxalate production in the body. By inhibiting LDHA, nedosiran aims to reduce the production of oxalate, thereby addressing the underlying cause of primary hyperoxaluria type 3. 

Spectrum: The spectrum of nedosiran’s action is limited to the treatment of primary hyperoxaluria type 3 (PH3), a rare genetic disorder. PH3 is characterized by mutations in the HOGA1 gene, leading to the overproduction of oxalate, which results kidney stones formation and other complications, including kidney damage. nedosiran’s therapeutic spectrum focuses on addressing the specific biochemical abnormalities associated with PH3. It is not used for other medical conditions or as a general treatment. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Erythema 

Bruising  

Pain  

Rash 

Black Box Warning

Black Box Warning: 

There was no specific black box warning associated with the nedosiran. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: Patients with a known hypersensitivity or severe allergic reaction to nedosiran or any of its components should not receive the medication. 
• Interference with RNAi Mechanism: Any condition or medication that interferes with the RNAi mechanism used by nedosiran may be a contraindication. This includes conditions or medications that inhibit the delivery or functioning of the RNAi therapeutic. 
• Pregnancy and Breastfeeding: The safety of nedosiran during pregnancy and lactation may not be well-established. Therefore, it may be contraindicated in pregnant women or nursing mothers unless the potential benefits clearly outweigh the risks. 
• Severe Liver or Kidney Dysfunction: nedosiran is primarily eliminated through the liver and kidneys. Patients with severe liver or kidney dysfunction may not be suitable candidates for nedosiran therapy, and dosing adjustments or alternative treatments may be necessary.

Caution: 

• Drug Interactions: Potential drug interactions with concomitant medications should be evaluated. Certain medications may interfere with the efficacy or safety of nedosiran. Healthcare providers should be aware of any drugs that patients are taking concurrently. 
• Pediatric and Geriatric Populations: nedosiran’s safety and efficacy in pediatric and geriatric populations may differ from those in adults. Special consideration should be given to dosing, monitoring, and individual patient characteristics in these age groups.

Comorbidities: 

• Chronic Kidney Disease (CKD): Patients with PH3 may develop kidney stones and, in some cases, kidney damage. Individuals with pre-existing CKD may require close monitoring and management of their kidney function while receiving nedosiran. 
• Liver Disease: As nedosiran is metabolized in the liver, patients with liver disease or impairment may need careful monitoring and potential dose adjustments to ensure safe and effective treatment. 
• Immunosuppression: Some patients with PH3 may have received kidney transplants and are on immunosuppressive therapy to prevent organ rejection. Healthcare providers should consider the potential for interactions between nedosiran and immunosuppressive medications. 

Pregnancy / Lactation

Pregnancy consideration:  

pregnancy category: not assigned  

Lactation: excreted into breast milk: unknown  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• <b>Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.   
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

nedosiran is an investigational RNA-based therapy designed to target the underlying cause of primary hyperoxaluria type 3 (PH3). Its pharmacology centers on the inhibition of lactate dehydrogenase A, a key enzyme involved in the glyoxylate pathway. In individuals with PH3, genetic mutations lead to overproduction of oxalate, which can result in kidney stones and kidney damage.

nedosiran works by reducing the production of oxalate through the specific inhibition of LDHA. By targeting this enzyme, nedosiran aims to lower oxalate levels in the body, potentially mitigating the progression of PH3 and its associated complications. nedosiran’s mechanism of action addresses the underlying biochemical abnormality of PH3, representing a promising therapeutic approach for this rare genetic disorder.  

Pharmacodynamics: 

• Reduction of Oxalate Production: In individuals with PH3, genetic mutations lead to the overproduction of oxalate, a substance that can form kidney stones and potentially lead to kidney damage. nedosiran’s primary pharmacological effect is the reduction of oxalate production by inhibiting LDHA. 
• Lowering Urinary Oxalate Levels: By inhibiting LDHA, nedosiran aims to reduce the levels of oxalate in the urine, which is a hallmark of PH3. Lower urinary oxalate levels may help prevent the formation of kidney stones and mitigate kidney damage. 
• Potential Disease Modification: The pharmacodynamics of nedosiran are focused on potentially modifying the course of PH3 by addressing the underlying biochemical abnormality. It does not provide a cure but rather aims to manage the condition and its complications.

Pharmacokinetics: 

Absorption 

nedosiran is typically administered through subcutaneous injection. Subcutaneous administration allows for the drug to be absorbed gradually into the bloodstream from the injection site. The rate of absorption depends on factors such as injection technique and individual patient factors. 

Distribution 

Once absorbed into the bloodstream, nedosiran is expected to distribute throughout the body, including to target tissues relevant to PH3. Distribution may vary depending on factors like tissue perfusion and the specific sites where oxalate metabolism occurs. 

Metabolism 

nedosiran is a synthetic RNA-based therapeutic designed to target the LDHA enzyme in the glyoxylate pathway. It is not metabolized in the same way as small-molecule drugs. Instead, it exerts its pharmacological effect by inhibiting the LDHA enzyme, thereby reducing the production of oxalate. 

Elimination and excretion 

As an RNA-based therapy, nedosiran is not subject to the same excretion pathways as small-molecule drugs. It is not primarily metabolized in the liver or excreted through the kidneys. 

Adminstartion

Administration: 

• Injection Site: The subcutaneous injection is typically administered in areas with adequate subcutaneous fat, such as the thigh, abdomen, or upper arm. The exact injection site may vary, but it should be chosen based on the healthcare provider’s instructions. 
• Preparation: The healthcare provider will prepare the injection site by cleaning it with an antiseptic solution to reduce the risk of infection. 
• Needle and Syringe: A fine-gauge needle and syringe are used to administer the injection. The specific needle size and syringe volume will be determined by the healthcare provider. 
• Administration: The healthcare provider will insert the needle into the subcutaneous tissue and inject the nedosiran solution. The rate of injection and depth of needle insertion will be based on standard injection techniques. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: nedosiran 

Pronounced: (neh-DOH-suh-ran)  

Why do we use nedosiran? 

nedosiran is primarily being investigated as a potential therapy for individuals with PH3. PH3 is caused by genetic mutations that lead to increased oxalate production. nedosiran works by inhibiting lactate dehydrogenase A (LDHA), a key enzyme in the glyoxylate pathway, to reduce oxalate production.

By targeting the underlying biochemical abnormality, nedosiran aims to lower oxalate levels in individuals with PH3, potentially preventing the formation of kidney stones and reducing the risk of kidney damage.