Lokelma Mechanism of Action

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphatemia. ATC code: V03AE10.
Pharmacology: Pharmacodynamics: Mechanism of action: Sodium zirconium cyclosilicate is a non-absorbed, non-polymer inorganic powder with a uniform micropore structure that preferentially captures potassium in exchange for hydrogen and sodium cations. Sodium zirconium cyclosilicate is highly selective for potassium ions, even in the presence of other cations, such as calcium and magnesium, in vitro. Sodium zirconium cyclosilicate captures potassium throughout the entire gastrointestinal (GI) tract and reduces the concentration of free potassium in the GI lumen, thereby lowering serum potassium levels and increasing faecal potassium excretion to resolve hyperkalaemia.
Pharmacodynamic effects: Sodium zirconium cyclosilicate starts reducing serum potassium concentrations as soon as 1 hour after ingestion and normokalaemia can be achieved typically within 24 to 48 hours. Sodium zirconium cyclosilicate does not affect serum calcium or magnesium concentrations, or urinary sodium excretion. There is a close correlation between starting serum potassium levels and effect size; patients with higher starting serum potassium levels have greater reductions in serum potassium. There is a reduction in urinary potassium excretion which is a consequence of a reduction in serum potassium concentration. In a study of healthy subjects given Lokelma 5 g or 10 g once daily for four days, dose-dependent reduction in serum potassium concentration and total urinary potassium excretion were accompanied by mean increases in faecal potassium excretion. No statistically significant changes in urinary sodium excretion were observed.
There were no studies conducted to investigate the pharmacodynamics when sodium zirconium cyclosilicate is administered with or without food.
Sodium zirconium cyclosilicate has also been shown to bind ammonium in vitro and in vivo, thereby removing ammonium and increasing serum bicarbonate levels. Lokelma-treated patients experienced an increase of 1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 g once daily in bicarbonate compared with a mean increase of 0.6 mmol/L for those receiving placebo. In an environment where other factors affecting renin and aldosterone were not controlled, Lokelma demonstrated a dose-independent change in mean serum aldosterone levels (range: -30% to -31%) compared with the placebo group (+14%). No consistent effect on systolic and diastolic blood pressure has been observed.
In addition, mean reductions in blood urea nitrogen (BUN) were observed in the 5 g (1.1 mg/dL) and 10 g (2.0 mg/dL) three times daily groups compared with small mean increases in the placebo (0.8 mg/dL) and low dose sodium zirconium cyclosilicate (0.3 mg/dL) groups.
Clinical efficacy and safety: The potassium-lowering effects of Lokelma have been demonstrated in three randomised, double-blind, placebo-controlled trials in patients with hyperkalaemia. All three studies tested the initial effect of Lokelma to correct hyperkalaemia during a 48-hour period and two studies also tested maintenance of normokalaemia effect obtained. The maintenance studies included patients with chronic kidney disease (58%), heart failure (10%), diabetes mellitus (62%) and RAAS inhibitor therapy (68%). In addition, two open-label maintenance studies tested long-term safety of Lokelma. These five studies included 1760 patients given doses of Lokelma; 507 exposed for at least 360 days. In the studies, Lokelma reduced serum potassium and maintained normal serum potassium levels regardless of the underlying cause of hyperkalaemia, age, sex, race, comorbid disease or concomitant use of RAAS inhibitors. No dietary restrictions were imposed; patients were instructed to continue their usual diet without any specified alterations.
Study 1: A two-phase, placebo-controlled correction and maintenance use study: A two-part, double-blind, randomised, placebo-controlled clinical trial of 753 patients (mean age of 66 years, range 22 to 93 years) with hyperkalaemia (5 to ≤ 6.5 mmol/L, baseline potassium average 5.3 mmol/L), and included patients with chronic kidney disease, heart failure, diabetes mellitus and those on RAAS inhibitor therapy.
During the correction phase, patients were randomised to receive Lokelma (1.25 g, 2.5 g, 5 g or 10 g) or placebo, administered three times daily for the initial 48 hours (Table 1). (See Table 1.)

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Lokelma 10 g administered three times daily lowered serum potassium by 0.7 mmol/L at 48 hours (p <0.001 vs. placebo); statistically significant 14% potassium reduction was observed 1 hour after the first dose. Patients with higher starting potassium levels had a greater response to Lokelma. Patients with pre-treatment potassium levels in excess of 5.5 mmol/L (average baseline 5.8 mmol/L) saw an average decrease of 1.1 mmol/L at 48 hours while those with starting potassium levels at or below 5.3 mmol/L had an average decrease of 0.6 mmol/L at the highest dose.
Patients who became normokalaemic after receiving Lokelma during the correction phase were re-randomised to receive once daily placebo or once daily Lokelma at the same dose level as they had received three times daily during the correction phase (Table 2). (See Table 2.)

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At the end of the maintenance period, when Lokelma was no longer administered, average potassium levels increased to near baseline levels.
Study 2: A multi-phase, placebo-controlled maintenance study with an additional open-label phase: In the correction phase of the study, 258 patients with hyperkalaemia (baseline average 5.6, range 4.1 - 7.2 mmol/L) received 10 g of Lokelma administered three times daily for 48 hours. Reductions in potassium were observed 1 hour after the first 10 g dose of Lokelma. Median time to normokalaemia was 2.2 hours with 66% of patients achieving normokalaemia at 24 hours and 88% at 48 hours. Responses were larger in patients with more severe hyperkalaemia; serum potassium fell 0.8, 1.2 and 1.5 mmol/L in patients with baseline serum potassium < 5.5, 5.5-5.9 and ≥ 6 mmol/L, respectively.
Patients who achieved normokalaemia (potassium levels between 3.5 and 5 mmol/L) were randomised in a double-blind fashion to one of three doses of Lokelma [5 g (n=45), 10 g (n=51), or 15 g (n=56)] or placebo (n=85) administered once daily for 28 days (the double-blind randomised withdrawal phase).
The proportion of subjects with average serum potassium < 5.1 mmol/L from Study Day 8 to 29 (three-week period) was greater at the 5 g, 10 g and 15 g once daily doses of Lokelma (80%, 90% and 94%, respectively), compared with placebo (46%). There was a mean decrease in serum potassium of 0.77 mmol/L, 1.10 mmol/L, 1.19 mmol/L and 0.44 mmol/L, respectively, and the proportion of subjects who remained normokalaemic was 71%, 76%, 85% and 48% in the 5 g, 10 g, 15 g once daily doses of Lokelma and placebo groups, respectively.
Maintenance phase with Lokelma titration (open-label) results: 123 patients entered the 11-month open-label phase. The proportion of subjects with average serum potassium < 5.1 mmol/L was 88%, the average serum potassium level was 4.66 mmol/L and the proportion of serum potassium measurements below 3.5 mmol/L was less than 1%; between 3.5 and 5.1 mmol/L was 77%; or between 3.5 and 5.5 mmol/L was 93%, irrespective of other factors that might influence the serum potassium. Treatment was discontinued on study exit (Day 365).
Kaplan-Meier estimates of time to relapse for maintenance phase showed dose dependence in time to relapse with median time for 5 g dose ranging from 4 to 21 days depending on the baseline serum potassium values. Serum potassium should be monitored periodically and the Lokelma dose titrated as described in Dosage & Administration.
Figure 1 illustrates the mean serum potassium over the correction and maintenance phases of the study. (See Figure 1.)

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Study 3: A study in chronic kidney disease patients with hyperkalaemia: This study was a double-blind placebo-controlled dose-escalating study in 90 patients (60 Lokelma patients; 30 controls) with baseline eGFR between 30 - 60 ml/min/1.73 m² and hyperkalaemia (baseline serum potassium 5.2 mmol/L, range 4.6 - 6 mmol/L). Patients were randomised to receive escalating doses of Lokelma (0.3 g, 3 g and 10 g) or placebo, administered three times a day with meals for two to four days. The primary endpoint was the rate of change in serum potassium from baseline throughout the initial 2 days of treatment. The trial met the primary efficacy endpoint at the 3 g and 10 g doses of Lokelma compared to placebo. Lokelma at the 10 g dose and the 3 g dose resulted in mean maximal reductions of 0.92 mmol/L and 0.43 mmol/L, respectively. Twenty-four hour urine collections showed that Lokelma decreased urinary potassium excretion from baseline by 15.8 mmol/24 h compared to placebo increase by 8.9 mmol/24 h (p < 0.001). Sodium excretion was unchanged relative to placebo (10 g, increase by 25.4 mmol/24 h compared to placebo increase by 36.9 mmol/24 h (NS)).
Study 4: A two-phase, multicenter, multi-dose, open-label safety and efficacy study: The long term (up to 12 months) effects of Lokelma were assessed in this study in 751 subjects with hyperkalaemia (baseline average 5.59 mmol/L; range 4.3-7.6 mmol/L). Comorbid conditions included chronic kidney disease (65%), diabetes mellitus (64%), heart failure (15%) and hypertension (83%). Use of diuretics and RAAS inhibitors was reported by 51 and 70% of subjects, respectively. During the correction phase, 10 g of Lokelma was administered three times daily for at least 24 hours and up to 72 hours. Subjects who achieved normokalaemia (3.5-5.0 mmol/L, inclusive) within 72 hours entered the maintenance phase of the study. All subjects in the maintenance phase received Lokelma at a starting dose of 5 g once daily which could be increased in increments of 5 g once daily (to a maximum of 15 g once daily) or decreased (to a minimum of 5 g once every other day) based upon the titration regimen.
Normokalaemia was achieved in 494/748 (66%), 563/748 (75%) and 583/748 (78%) of subjects after 24, 48 and 72 hours of correction phase dosing with an average reduction in serum potassium of 0.81 mmol/L, 1.02 mmol/L and 1.10 mmol/L at 24 (n=748), 48 (n=104) and 72 (n=28) hours, respectively. Normokalaemia was dependent on baseline potassium concentration, with subjects with the highest baseline serum potassium concentrations having the most prominent decrease after starting the study drug but with the lowest proportion of subjects achieving normokalaemia. One hundred and twenty-six patients had a baseline serum potassium ≥ 6.0 mmol/L (mean baseline potassium 6.28 mmol/L). These subjects had a mean reduction of 1.37 mmol/L at the end of the correction phase. (See Table 3.)

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Normokalaemia was maintained while patients remained on drug and the mean serum potassium increased following discontinuation. Among those patients using RAAS inhibitors at baseline, 89% did not discontinue RAAS inhibitor therapy, 74% were able to maintain the same dose during the maintenance phase and among those not on RAAS inhibitors at baseline, 14% were able to initiate this therapy. During maintenance phase, 75.6% of subjects maintained normokalaemia, despite use of RAAS inhibitors.
Figure 2 illustrates the mean serum potassium over the correction and maintenance phases of the study. (See Figure 2.)

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Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with Lokelma in one or more subsets of the paediatric population in male and female children from birth to less than 18 years of age, with hyperkalaemia (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In addition, clinical studies have shown it not to be systemically absorbed. An in vivo mass balance study in rats showed that sodium zirconium cyclosilicate was recovered in the faeces with no evidence of systemic absorption. Due to these factors and its insolubility, no in vivo or in vitro studies have been performed to examine its effect on cytochrome P450 (CYP450) enzymes or transporter activity.
Elimination: Sodium zirconium cyclosilicate is eliminated via the faeces.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.