Tell me about Lokelma (sodium zirconium cyclosilicate) for hyperkalaemia management in adults.

Lokelma (Sodium Zirconium Cyclosilicate) for Hyperkalemia Management

Mechanism and Pharmacology

Lokelma is a highly selective, non-absorbed potassium binder that exchanges hydrogen and sodium for potassium throughout the entire gastrointestinal tract, increasing fecal potassium excretion. 1, 2, 3

• The compound is a non-polymer zirconium silicate crystal that also binds ammonium ions in exchange for sodium and hydrogen 2, 3
• Unlike older agents, Lokelma works throughout the entire GI tract, not just the colon 3
• It is not systemically absorbed, minimizing systemic drug interactions 2, 3

Dosing and Administration

Initial Treatment Phase

For acute hyperkalemia, administer 10 g three times daily for up to 48 hours to rapidly lower serum potassium. 1

• Mix the entire packet contents in approximately 3 tablespoons of water, stir well, and drink immediately 1
• If powder remains, add more water and repeat until the full dose is consumed 1
• Normokalaemia (3.5-5.0 mmol/L) is typically achieved within 24-48 hours in most patients 4, 2
• Significant reductions in serum potassium occur within 1 hour of a single 10 g dose, with mean reductions of approximately 1.1 mEq/L over 48 hours 4, 5

Maintenance Phase

After achieving normokalaemia, continue with 10 g once daily and adjust based on serum potassium levels. 1

• The maintenance dose range is 5 g every other day to 15 g daily 1
• Titrate in 5 g increments at intervals of 1 week or longer based on serum potassium levels 1
• Monitor serum potassium after one week during initiation and after any dose adjustment 5, 6
• Decrease or discontinue if serum potassium falls below the desired target range 1

Special Population: Hemodialysis Patients

For patients on chronic hemodialysis, administer Lokelma only on non-dialysis days, starting with 5 g once daily. 1

• Consider a starting dose of 10 g once daily on non-dialysis days if serum potassium exceeds 6.5 mEq/L 1
• Adjust based on pre-dialysis potassium values after the long inter-dialytic interval 1
• The maintenance dose range is 5-15 g once daily on non-dialysis days 1
• In the DIALIZE study, once-daily Lokelma on non-dialysis days effectively maintained normal pre-dialysis serum potassium levels over 8 weeks 4

Clinical Efficacy

Acute Correction

Lokelma achieves normokalaemia in 82% of patients within 24 hours and nearly 100% within 48-72 hours, regardless of baseline kidney function. 7

• In patients with severe hyperkalemia (≥6.0 mEq/L), significant reductions occur within 1 hour 4
• The potassium-lowering effect is consistent across all patient subgroups, including those with chronic kidney disease, diabetes, heart failure, and those on RAAS inhibitor therapy 2
• Efficacy is maintained regardless of CKD stage, with similar response rates in patients with eGFR <30 versus ≥30 mL/min/1.73 m² 7

Long-Term Maintenance

Once-daily Lokelma maintains normokalaemia in 82-90% of patients for up to 12 months. 8, 7

• In the HARMONIZE extension study, 88.3% of patients maintained mean serum potassium ≤5.1 mmol/L for up to 11 months 8
• The median daily maintenance dose was 10 g (range 2.5-15 g) 8
• Long-term efficacy is sustained across all CKD stages, with 82% of patients with eGFR <30 mL/min/1.73 m² maintaining normokalaemia at Day 365 7

Enabling RAAS Inhibitor Therapy

Lokelma allows continuation and optimization of life-saving RAAS inhibitor therapy in patients with cardiovascular disease and chronic kidney disease who develop hyperkalemia. 5, 6

• Discontinuation of RAAS inhibitors leads to adverse cardiorenal outcomes and increased mortality 5, 6
• The 2022 AHA/ACC/HFSA Heart Failure Guidelines provide Class I, Level A evidence that Lokelma enables maintenance of RAAS inhibitors in heart failure patients 5
• Potassium-lowering efficacy is maintained irrespective of concomitant RAAS inhibitor use 3
• In the PEARL-HF trial, Lokelma enabled 86% of patients to remain on spironolactone 50 mg daily versus 66% with placebo 5

Safety Profile and Adverse Effects

Common Adverse Effects

The most common adverse effects are gastrointestinal symptoms (constipation, diarrhea, nausea) and dose-dependent edema. 5, 6

• Edema incidence increases with dose: 2% with 5 g, 6% with 10 g, and 14% with 15 g daily 5, 6
• Monitor for peripheral edema due to the sodium content of Lokelma 5
• Gastrointestinal adverse events are generally mild to moderate 4, 2
• Hypokalemia can occur but incidence is low; regular monitoring is essential 4, 2

Sodium Content

Each 10 g dose contains approximately 1200 mg of sodium during the correction phase and 400-1200 mg sodium daily during maintenance. 5, 6

• Each 5 g dose contains approximately 400 mg of sodium, though the extent of patient absorption is unknown 1
• Monitor patients with heart failure or fluid-sensitive conditions for edema 5, 1
• In clinical trials, edema was generally mild to moderate and more common with the 15 g once-daily dose 1

Serious Adverse Events

Lokelma has not been associated with serious adverse events such as intestinal necrosis or colonic ischemia in randomized trials. 4

• No serious gastrointestinal complications have been reported, unlike sodium polystyrene sulfonate 4, 5
• The safety profile remained consistent over 12 months of treatment 2, 8
• Tolerability was generally similar to placebo in controlled trials 2

Additional Benefits

Metabolic Acidosis

Sustained increases in serum bicarbonate have been observed with Lokelma, providing added benefit for patients with metabolic acidosis. 4, 7

• Mean serum bicarbonate increased during the maintenance phase in long-term studies 7
• This effect may be particularly beneficial in CKD patients who commonly have metabolic acidosis 4

Drug Interactions and Administration Timing

Administer other oral medications at least 2 hours before or 2 hours after Lokelma to avoid reduced absorption. 1

• Lokelma can bind other medications throughout the GI tract, reducing their absorption 5
• The low potential for drug interactions is due to its non-absorbed nature 3
• Unlike patiromer, which requires 3-hour separation, Lokelma requires only 2-hour separation 1

Contraindications and Precautions

Gastrointestinal Motility Disorders

Avoid Lokelma in patients with severe constipation, bowel obstruction, or impaction, as it has not been studied in these conditions and may worsen gastrointestinal symptoms. 1

• Also avoid in patients with abnormal post-operative bowel motility disorders 1
• Lokelma may be ineffective in these populations 1

Not for Emergency Use

Lokelma should not be used as emergency treatment for life-threatening hyperkalemia due to its delayed onset of action. 5, 6, 1

• Onset begins at 1-2 hours, which is too slow for life-threatening situations 5
• For life-threatening hyperkalemia, use insulin/glucose, beta-agonists, or dialysis first 5
• After initial stabilization, Lokelma can be initiated for ongoing management 6

Monitoring Protocol

Check serum potassium within 1 week of starting Lokelma or after any dose adjustment to avoid hypokalemia and guide titration. 5, 6

• Regular monitoring is essential to prevent overcorrection 6
• Monitor for peripheral edema due to dose-dependent risk 5
• In hemodialysis patients, assess serum potassium after one week during initiation and after dose adjustments 1

Comparative Advantages Over Older Agents

Versus Sodium Polystyrene Sulfonate (Kayexalate)

Lokelma is preferred over Kayexalate due to superior efficacy, better safety profile, and improved patient tolerability. 5, 6

• Kayexalate is linked to serious gastrointestinal complications including intestinal ischemia and colonic necrosis, with an overall mortality of approximately 33% 5
• Kayexalate can induce hypocalcemia and hypomagnesemia due to non-selective cation binding, while Lokelma is highly selective for potassium 5
• Lokelma's efficacy is supported by multiple robust clinical trials, whereas Kayexalate has only one small 7-day randomized trial 5
• Lokelma is more palatable than Kayexalate, facilitating better adherence 5, 6
• Clinical data for Kayexalate remains limited compared to the well-documented efficacy of Lokelma 5

Versus Patiromer

Lokelma has a faster onset of action (1-2 hours) compared to patiromer (7 hours), making it superior when rapid potassium reduction is needed. 5, 6

• Both agents are recommended as first-line potassium binders by the American College of Cardiology, with Lokelma preferred when faster onset is needed 6
• Lokelma requires only 2-hour separation from other medications versus 3 hours for patiromer 1
• Patiromer causes hypomagnesemia and requires magnesium monitoring, while Lokelma does not 5

Clinical Scenarios for Use

Chronic Hyperkalemia Management

Initiate Lokelma in patients on RAAS inhibitors with potassium 5.0-6.5 mEq/L while maintaining RAAS inhibitor therapy. 5, 6

• This approach preserves the cardiovascular and renal protective effects of RAAS inhibitors 5
• Maintaining RAAS inhibitor therapy with Lokelma is clinically important because discontinuation is associated with adverse cardiorenal outcomes 5

Dietary Considerations

Patients with chronic kidney disease should continue a potassium-restricted diet while receiving Lokelma, though restrictions may be less stringent than without binder therapy. 5

• In pediatric CKD patients, Lokelma use was associated with liberalization of dietary potassium restriction 9
• Evidence linking dietary potassium intake to serum levels is limited, and potassium-rich diets provide cardiovascular benefits 5

Long-Term Outcomes

Lokelma maintains consistent efficacy and safety for up to 12 months of continuous treatment. 2, 8, 7

• In the 11-month HARMONIZE extension, 64.2% of patients completed the study, demonstrating good long-term tolerability 8
• No new safety concerns emerged during long-term treatment 8
• The potassium-lowering effect was sustained throughout the maintenance phase 7