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Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

ABSTRACT: Potassium (K⁺ ) is the main intracellular cation in the body. Elevated K⁺ levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K⁺ homeostasis and the effects of orally administered K⁺ binders, such as sodium zirconium cyclosilicate (SZC), on K⁺ redistribution and excretion in patients remain incompletely understood. We built a fit-for-purpose systems pharmacology model to describe K⁺ homeostasis in hyperkalemic subjects and capture serum K⁺ (sK⁺ ) dynamics in response to acute and chronic administration of SZC. The resulting model describes K⁺ distribution in the gastrointestinal (GI) tract, blood, and extracellular and intracellular spaces of tissue, renal clearance of K⁺ , and K⁺ -SZC binding and excretion in the GI tract. The model, which was fit to time-course sK⁺ data for individual patients from two clinical trials, accounts for bolus delivery of K⁺ in meals and oral doses of SZC. The virtual population of patients derived from fitting the model to these trials was then modified to predict the SZC dose-response and inform clinical trial design in two new applications: emergency lowering of sK⁺ in severe hyperkalemia and prevention of hyperkalemia between dialysis sessions in patients with end-stage chronic kidney disease. In both cases, the model provided novel and useful insight that was borne out by the now completed clinical trials, providing a concrete case study of fit-for-purpose, model-informed drug development after initial approval of a drug.

SUBMITTER: Clegg LE

PROVIDER: S-EPMC10864923 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

Clegg Lindsay E LE Chu Lulu L Nagard Mats M Boulton David W DW Penland Robert C RC

CPT: pharmacometrics & systems pharmacology 20231204 2

Potassium (K+ ) is the main intracellular cation in the body. Elevated K+ levels (hyperkalemia) increase the risk of life-threatening arrhythmias and sudden cardiac death. However, the details of K+ homeostasis and the effects of orally administered K+ binders, such as sodium zirconium cyclosilicate (SZC), on K+ redistribution and excretion in patients remain incompletely understood. We built a fit-for-purpose systems pharmacology model to d ...[more]

PMID: 38050337

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Project description:BackgroundOral sodium zirconium cyclosilicate (SZC) is a novel potassium binder capable of achieving a rapid reduction of serum potassium (sK+) and maintaining a long-term normokalemia. We undertook a meta-analysis to summarize and evaluate the effects surrounding SZC in patients with hyperkalemia.MethodWe searched data sources from MEDLINE (from 1950 to Sep 2020), EMBASE (from 1970 to Sep 2020), and the Cochrane Library database (from 1950 to Sep 2020) for eligible studies. All randomized controlled trials (RCTs) regarding comparison of therapeutic effects of SZC in hyperkalemia participants were included.ResultsSeven studies, including 1697 patients with hyperkalemia, were analyzed. SZC significantly reduced mean sK+ (-0.42 mmol/L; 95% CI: -0.63 to -0.20 mmol/L, p = 0.0001) compared with placebo, with a significantly greater proportion of patients with normokalemia (RR 3.48, 95% CI 1.49 to 8.11, p = 0.004). Subgroup analyses showed that the longer durations of SZC treatment, the greater magnitudes of potassium reduction when compared with those of placebo (p between subgroups = 0.01) at correction phase. Besides, it also demonstrated sK+ tended to decrease more in patients who got longer treatment or larger dosage of SZC at maintenance phase; however, the difference did not reach statistical significance. Additionally, the drug was equally effective in studies with larger than 50% of patients with chronic kidney disease (CKD) or diabetes or patients using renin-angiotensin aldosterone system inhibitor (RAAS) inhibitors (all p < 0.05). The risk of edema (4.30, 1.17 to 15.84; p = 0.03) in SZC group was higher than those of placebo group. No statistically significant differences in the risks of other adverse events were observed between the two groups.ConclusionsSZC effectively decreased the sK+ level in patients with hyperkalemia within 48 h and had benefits in the long-term control of serum potassium in patients who continued to receive SZC with a favorable safety profile from available data.

Project description:BackgroundSodium zirconium cyclosilicate (SZC) reduces serum potassium in patients with chronic hyperkalaemia in clinical trials, but its role in the emergency treatment of hyperkalaemia is unproven. We hypothesized that SZC use for emergent hyperkalaemia would be associated with a reduction in rates of emergency interventions for hyperkalaemia.MethodsThis was a single-centre, propensity score-weighted case-control study of patients admitted with hyperkalaemia to a specialist renal centre. We randomly selected 250 patients admitted between April 2021 and September 2022 (post-SZC era) with a potassium level ≥5.5 mmol/l treated with at least one ≥10 g dose of SZC (treatment group). We randomly selected a comparator group of 250 patients admitted between January 2018 and December 2019 (pre-SZC era) with a potassium level ≥5.5 mmol/l (control group). Baseline demographic and clinical characteristics were recorded and used as covariates for propensity scoring and inverse probability treatment weighting (IPTW). Our primary outcome measure, rates of emergency haemodialysis (HD), was tested using unadjusted models and multivariable logistic regression models on unweighted data in addition to unadjusted models on weighted data. We also reviewed rates of emergency temporary central venous access as a secondary outcome.ResultsA total of 59% were male, the mean age was 67 years (standard deviation 14) and 149 (30%) were receiving maintenance dialysis. IPTW achieved satisfactory balance of covariates between the treatment and control groups. In the treatment group, patients were 77% less likely to need emergency HD {odds ratio [OR] 0.23 [confidence interval (CI) 0.17-0.31]}. This result was consistent following analysis of weighted and unweighted data. Similarly, patients treated with SZC were 73% less likely to require emergency temporary central venous access [OR 0.27 (CI 0.20-0.36)].ConclusionSZC was associated with a significant reduction in the rates of emergency HD and emergency temporary central venous access in patients admitted to a specialized renal centre with emergent hyperkalaemia.

Project description:BACKGROUND AND OBJECTIVES:Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. RESULTS:Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS:After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

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Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

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Potassium homeostasis and therapeutic intervention with sodium zirconium cyclosilicate: A model-informed drug development case study.

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