Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products; Drugs for treatment of hyperkalaemia and hyperphosphatemia, ATC code: V03AE10

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 addition, the efficacy and safety of Lokelma was studied in a double-blind, placebo-controlled trial of 196 chronic haemodialysis patients with hyperkalaemia, who received doses of Lokelma for 8 weeks. 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 2).

Table 2. Correction phase (Study 1): Percentage of normokalaemic subjects after 48 hours of Lokelma

Lokelma dose (three times daily)
Placebo      1.25 g       2.5 g         5g         10 g
N                                          158          154          141           157        143 Baseline serum potassium, mmol/L           5.3          5.4          5.4           5.3        5.3 Normokalaemic at 48 hours, %               48           51           68            78         86 p-value vs. placebo                                     NS           < 0.001       < 0.001    < 0.001 NS: not significant

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 3).

Table3. Maintenance phase (12 days, Study 1): Mean number of normokalaemic days Maintenance phase treatment (once daily)
Placebo            Lokelma             P-value vs.
placebo

Correction phase Lokelma dose          n         Days     n         Days 1.25 g three times daily               41        7.6      49        7.2       NS 2.5 g three times daily                46        6.2      54        8.6       0.008
5 g three times daily                  68        6.0      64        9.0       0.001 10 g three times daily                 61        8.2      63        10.2      0.005 NS: not significant

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 section 4.2.

Figure 1 illustrates the mean serum potassium over the correction and maintenance phases of the study.



Figure 1. Correction and maintenance phases (Study 2): mean serum potassium over time with 95% CI

Mean Serum Potassium with 95% CI (mmol/L)



Exit=Last Visit within 1 day of Last Dose, EOS=End of Study (7 days +/- 1 day after Last Dose) *Given three times daily


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/1.73m2 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.

Table 4. Correction phase (Study 4): proportion of subjects with serum potassium concentrations between 3.5 and 5.0 mmol/L, inclusive, or between 3.5 and 5.5 mmol/L, inclusive, by correction phase study day - ITT population
Lokelma 10 g three times daily (N=749)
Serum potassium 3.5 to 5.0 mmol/L,                      Serum potassium 3.5 to 5.5 mmol/L, Correction Phase (CP) inclusive                                               inclusive n/N     Proportion       95% CI                        n/N     Proportion       95% CI CP at 24 hours                    494/748     0.660        0.625, 0.694                  692/748      0.925       0.904, 0.943 CP at 48 hours                    563/748     0.753        0.720, 0.783                  732/748      0.979       0.965, 0.988 CP at 72 hours/CP Last            583/748     0.779        0.748, 0.809                  738/748      0.987       0.976, 0.994 Note: One subject had a post-dose value that was more than 1 day after last dose. Therefore, the subject was eligible for the Correction Phase ITT Population; however, the time point was excluded from the analysis.

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.

Figure 2: Correction and maintenance phases in 12-month open-label study (Study 4) - mean serum potassium over time with 95% CI



CPBL=Correction Phase Baseline, MPBL=Maintenance Phase Baseline
Exit=Last Visit within 1 day of Last Dose, EOS=End of Study (7 days +/- 1 day after Last Dose) 
Study 5
A randomised, double-blind, placebo-controlled study in patients on chronic haemodialysis In this study, 196 patients (mean age 58 years, range 20 to 86 years) with end stage renal disease on stable dialysis for at least 3 months and persistent pre-dialysis hyperkalaemia were randomised to receive Lokelma 5 g or placebo once daily on non-dialysis days. At randomization, mean serum potassium levels were 5.8 mmol/L (range 4.2-7.3 mmol/L) in the Lokelma group and 5.9 mmol/L (range 4.2–7.3 mmol/L) in the placebo group. To achieve pre-dialysis serum potassium level between
4.0-5.0 mmol/L during the dose adjustment period (initial 4 weeks), the dose could be adjusted weekly in 5 g increments up to 15 g once daily based on pre-dialysis serum potassium measurement after the LIDI. The dose reached at the end of the dose-adjustment period was maintained throughout the subsequent 4-week evaluation period. At the end of the dose adjustment period, 37%, 43%, and 19% of patients were on Lokelma 5 g, 10 g and 15 g. The proportion of responders, defined as those subjects who maintained a pre-dialysis serum potassium between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments after LIDI and who did not receive rescue therapy during the evaluation period, was 41% in the Lokelma group, and 1% in the placebo group (p < 0.001) (see Figure 3).

In post-hoc analyses the number of times patients had serum potassium between 4.0 and 5.0 mmol/L after the LIDI during the evaluation period was higher in the Lokelma group. 24% of patients were within this range at all 4 visits in the Lokelma group and none in the placebo group. The post-hoc analysis showed the proportion of patients who maintained serum potassium level between 3.5 and 5.5 mmol/L on at least 3 out of 4 dialysis treatments after LIDI during the evaluation period was 70% in the Lokelma group and 21% in the placebo group.

At the end of treatment, the mean post-dialysis serum potassium level was 3.6 mmol/L (range 2.6-5.7 mmol/L) in Lokelma group and 3.9 mmol/L (range 2.2-7.3 mmol/L) in the placebo group. There were no differences between Lokelma and placebo groups in interdialytic weight gain (IDWG). IDWG was defined as pre-dialysis weight minus post-dialysis weight on the previous dialysis session and was measured after the LIDI.

Figure 3: Mean pre-dialysis serum potassium levels over time in patients on chronic dialysis



F/U- follow-up period
The displayed error bars correspond to 95% confidence intervals.
n = Number of patients with non-missing potassium measurements at a particular visit.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
Absorption
Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In addition, clinical trials 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 feces 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 feces.