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A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.

Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS - Kidney Int. (2015)

Bottom Line: Current therapies are poorly tolerated and not always effective.Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2.In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Indiana University Health Arnett, Lafayette, Indiana, USA.

ABSTRACT
Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.

No MeSH data available.


Related in: MedlinePlus

Rate of decline in serum potassium over the first 48 h of treatment with 0.3-g (n=12), 3-g (n=24), and 10-g ZS-9 (n=24) or placebo (n=30)—intent-to-treat population. This model prediction uses every serum K+ data point from each patient. Although the rate of decline is actually a curve, during the 48-h time frame of interest, it appears linear as presented here. The plotted rates of decline in serum K+ also visually illustrate the dose–response relationship. Triangles indicate study drug administration (six doses in 34 h). ZS-9, sodium zirconium cyclosilicate.
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fig2: Rate of decline in serum potassium over the first 48 h of treatment with 0.3-g (n=12), 3-g (n=24), and 10-g ZS-9 (n=24) or placebo (n=30)—intent-to-treat population. This model prediction uses every serum K+ data point from each patient. Although the rate of decline is actually a curve, during the 48-h time frame of interest, it appears linear as presented here. The plotted rates of decline in serum K+ also visually illustrate the dose–response relationship. Triangles indicate study drug administration (six doses in 34 h). ZS-9, sodium zirconium cyclosilicate.

Mentions: ZS-9 dose-dependently reduced in serum K+ (s-K+); the primary efficacy end point was met in the 3-g (P=0.048) and 10-g (P<0.0001) dose groups versus placebo (Figure 2). In the 10-g ZS-9 group, mean s-K+ decreased significantly from baseline by 0.11 mEq/l at 1 h after the first dose (P=0.02 vs. placebo). Greater mean reductions in s-K+ were seen on day 2 (Hour 28 to 48) with 10-g ZS-9 versus placebo (P⩽0.001), achieving a maximum reduction of 0.92 mEq/l at 38 h (P<0.001; Table 2, Figure 3). At Hour 38, 41.7% of patients on 10-g ZS-9 versus 3.4% on placebo had a >1.0 mEq/l drop in s-K+. The last dose in the 10-g ZS-9 group was administered on day 2, yet s-K+ remained significantly lower than placebo for 3.5 additional days (i.e., Hour 120; Figure 3).


A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.

Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS - Kidney Int. (2015)

Rate of decline in serum potassium over the first 48 h of treatment with 0.3-g (n=12), 3-g (n=24), and 10-g ZS-9 (n=24) or placebo (n=30)—intent-to-treat population. This model prediction uses every serum K+ data point from each patient. Although the rate of decline is actually a curve, during the 48-h time frame of interest, it appears linear as presented here. The plotted rates of decline in serum K+ also visually illustrate the dose–response relationship. Triangles indicate study drug administration (six doses in 34 h). ZS-9, sodium zirconium cyclosilicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526769&req=5

fig2: Rate of decline in serum potassium over the first 48 h of treatment with 0.3-g (n=12), 3-g (n=24), and 10-g ZS-9 (n=24) or placebo (n=30)—intent-to-treat population. This model prediction uses every serum K+ data point from each patient. Although the rate of decline is actually a curve, during the 48-h time frame of interest, it appears linear as presented here. The plotted rates of decline in serum K+ also visually illustrate the dose–response relationship. Triangles indicate study drug administration (six doses in 34 h). ZS-9, sodium zirconium cyclosilicate.
Mentions: ZS-9 dose-dependently reduced in serum K+ (s-K+); the primary efficacy end point was met in the 3-g (P=0.048) and 10-g (P<0.0001) dose groups versus placebo (Figure 2). In the 10-g ZS-9 group, mean s-K+ decreased significantly from baseline by 0.11 mEq/l at 1 h after the first dose (P=0.02 vs. placebo). Greater mean reductions in s-K+ were seen on day 2 (Hour 28 to 48) with 10-g ZS-9 versus placebo (P⩽0.001), achieving a maximum reduction of 0.92 mEq/l at 38 h (P<0.001; Table 2, Figure 3). At Hour 38, 41.7% of patients on 10-g ZS-9 versus 3.4% on placebo had a >1.0 mEq/l drop in s-K+. The last dose in the 10-g ZS-9 group was administered on day 2, yet s-K+ remained significantly lower than placebo for 3.5 additional days (i.e., Hour 120; Figure 3).

Bottom Line: Current therapies are poorly tolerated and not always effective.Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2.In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Indiana University Health Arnett, Lafayette, Indiana, USA.

ABSTRACT
Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.

No MeSH data available.


Related in: MedlinePlus