POTASSIUM-BINDING AGENTS FOR USE IN HEMODIALYSIS PATIENTS
20220218738 · 2022-07-14
Inventors
Cpc classification
International classification
Abstract
The present invention relates to the use of potassium-binding agents that are formulated to remove toxins, e.g., potassium ions, from the gastrointestinal tract at an elevated rate, without causing undesirable side effects, in hemodialysis patients. The compositions exhibit desired characteristics for the long term administration to treat or prevent the relapse or occurrence of certain conditions, for example hyperkalemia.
Claims
1. A method for treatment of hyperkalemia in a hemodialysis patient comprising administering a potassium-binding agent to a patient in need thereof.
2. The method of claim 1, where the potassium-binding agent is a microporous zirconium silicate.
3. The method of claim 1, where the potassium-binding agent is Sodium Zirconium Cyclosilicate.
4. The method of claim 1, where the potassium-binding agent is administered on non-dialysis days.
5. The method of claim 3, where the potassium-binding agent is administered in a 5 gram dose.
6. The method of claim 3, where the potassium-binding agent is administered in a 10 gram dose.
7. The method of claim 3, where the potassium-binding agent is administered in a 15 gram dose.
8. The method of claim 1, where the potassium-binding agent is administered on non-dialysis days.
9. The method of claim 1, where the potassium-binding agent is a 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form.
10. The method of claim 1, where the 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form is patiromer sorbitex calcium.
Description
LIST OF FIGURES
[0015]
[0016]
[0017]
[0018]
DETAILED DESCRIPTION
[0019] In one embodiment, the present disclosure involves administration of a suitable dose of a potassium-binding agent to a hemodialysis patient.
[0020] In one embodiment, the present disclosure involves administration of a suitable dose of microporous zirconium silicate to a hemodialysis patient.
[0021] In one embodiment, the present disclosure involves administration of a suitable dose of Sodium Zirconium Cyclosilicate to a hemodialysis patient.
[0022] In one embodiment, the present disclosure involves administration of a suitable dose of 2-fluoroacrylate-divinylbenzene-1,7-octadiene copolymer crosslinked in the salt or acid form to a hemodialysis patient.
[0023] In a further embodiment, the present disclosure involves administration of a suitable dose of patiromer sorbitex calcium to a hemodialysis patient.
[0024] In another embodiment, the present disclosure involves administration of a suitable dose of Sodium Zirconium Cyclosilicate to a hemodialysis patient pre-dialysis, i.e administration on non-dialysis days.
[0025] In one embodiment, the dosage of potassium-binding agent may range from 1-30 g, preferably 5-15 g, more preferably 5 g.
[0026] In another embodiment, the dosage of potassium-binding agent may range from 1-30 g, preferably 5-15 g, more preferably 10 g.
[0027] In another embodiment, the dosage of potassium-binding agent may range from 1-30 g, preferably 10-20 g, more preferably 15 g.
[0028] In another embodiment, the present disclosure involves administration of 5 grams of Sodium Zirconium Cyclosilicate to a hemodialysis patient pre-dialysis, i.e administration on non-dialysis days.
[0029] In another embodiment, the present disclosure involves administration of 10 grams of Sodium Zirconium Cyclosilicate to a hemodialysis patient pre-dialysis, i.e administration on non-dialysis days.
[0030] In another embodiment, the present disclosure involves administration of 15 grams of Sodium Zirconium Cyclosilicate to a hemodialysis patient pre-dialysis, i.e administration on non-dialysis days.
The use of zirconium silicate or titanium silicate microporous ion exchangers to remove toxic cations and anions from blood or dialysate is described in U.S. Pat. Nos. 6,579,460, 6,099,737, 6,332,985 and U.S. 2004/0105895, each of which is incorporated herein in their entirety. Additional examples of microporous ion exchangers are found in U.S. Pat. Nos. 6,814,871, 5,891,417, and 5,888,472, each of which is incorporated herein in their entirety.
Certain zirconium silicate compositions may exhibit undesirable effects when utilized in vivo for the removal of potassium in the treatment of hyperkalemia. Specifically, the inventors found that administration of zirconium silicate molecular sieve compositions is associated with an incidence of mixed leukocyte inflammation, minimal acute urinary bladder inflammation and the observation of unidentified crystals in the renal pelvis and urine in animal studies, as well as an increase in urine pH. These problems were addressed by controlling particle size and sodium content of the zirconium silicate compositions. See U.S. Pat. Nos. 8,802,152 and 8,808,750, each of which is incorporated herein in their entirety.
Further, certain zirconium silicate compositions have had issues with crystalline impurities and undesirably low cation exchange capacity. The reduction of more soluble forms of zirconium silicate is important to reduce or eliminate the systemic absorption of zirconium or zirconium silicate. This issue was addressed by controlling production conditions in a way that essentially eliminates ZS-8 from the composition, resulting in undetectable levels of ZS-8. See U.S. Pat. No. 8,877,255.
Certain zirconium silicate compositions are useful for long term use, for example, in the treatment of conditions associated with elevated levels of serum potassium. The use of zirconium silicate compositions in long term treatment regimens requires careful control of impurities, particularly lead, in the composition. For example, the FDA sets the acceptance criteria for lead in compositions for extended use at 5 micrograms per day. Certain zirconium silicates produced using known methods in industrial quantities contain approximately 1 to 1.1 ppm or more of lead. Even when zirconium silicate was prepared in smaller batches at higher purity, the level of lead was found to be 0.6 ppm or more.
Because zirconium silicate treatments utilize doses ranging from 5 to 45 grams per day, reduction in the level of lead is necessary. Compositions of zirconium silicate having lead content within an acceptable range necessitated by the daily doses of zirconium silicate are disclosed in US2017/0151279A1.
Sodium Zirconium Cyclosilicate is a cation exchange composition comprising a zirconium silicate of formula (I):
A.sub.pM.sub.xZr.sub.1-xSi.sub.nGe.sub.yO.sub.m (I)
where
[0031] A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof,
[0032] M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof,
[0033] “p” has a value from about 1 to about 20,
[0034] “x” has a value from 0 to less than 1,
[0035] “n” has a value from about 0 to about 12,
[0036] “y” has a value from 0 to about 12,
[0037] “m” has a value from about 3 to about 36 and 1≤n+y≤12,
[0038] wherein the composition exhibits a lead content below 0.6 ppm. Preferably, the lead content ranges from 0.1 and 0.6 ppm, more preferably from 0.3 to 0.5 ppm, and most preferably from 0.3 to 0.45 ppm. In one embodiment, the lead content is 0.38 ppm.
[0039] In addition to having a desired level of lead impurity, the composition may exhibit one or more properties that make it desirable as an orally ingested ion trap. In one aspect, the zirconium silicate composition may have a potassium exchange capacity exceeding 2.3 meq/g, preferably ranging from 2.3 to 3.5 meq/g, more preferably within the range of 3.05 and 3.35 meq/g, and most preferably about 3.2 meq/g. In one embodiment, 7% of the particles in the composition have a diameter less than 3 microns. In other embodiments less than 0.5% of the particles in the composition have a diameter less than 1 microns. Preferably, the sodium content is below 12% by weight, and more preferably 9% or less by weight. The zirconium silicate preferably exhibits an XRD diffractogram having the two highest peaks occur at approximately 15.5 and 28.9, with the highest peak occurring at 28.9. The material is preferably ZS-9, or predominately ZS-9, having a pH ranging from 7 to 9 and a potassium loading capacity between 2.7 and 3.7 mEq/g, and most preferably approximately 3.5.
EXAMPLES
[0040] A Phase 3b, Multicenter, Prospective, Randomized, Double Blind, Placebocontrolled Study to Reduce Incidence of Pre-Dialysis Hyperkalemia with Sodium Zirconium Cyclosilicate (SZC) The study was carried out to evaluate the efficacy of Sodium Zirconium Cyclosilicate in the treatment of hyperkalemia in patients on hemodialysis. The study was designed to include approximately 180 patients with ESRD receiving maintenance hemodialysis treatments three times per week with an indication for treatment of hyperkalemia (
[0041] The starting dose of SZC will be 5 g once daily on non-dialysis day and may be adjusted to a maximum of 15 g per non-dialysis day to maintain a pre-dialysis S-K between 4-5 mmol/L. SZC or placebo will be administered orally on non-dialysis days for a treatment period of eight weeks. Patients will be randomized (1:1) to double-blind treatment with either SZC or placebo, started at 5 g once daily on non-dialysis days, and titrated during a period of four weeks to achieve and maintain a pre-dialysis serum potassium between 4 and 5 mmol/L after the Long Inter-Dialytic Interval (LIDI). Maximum SZC dose is 15 g once daily on non-dialysis days. Treatment will be continued unchanged for an additional four week evaluation period to complete a total of 8 weeks. The primary benefit for patients randomized to SZC is expected to be the maintenance of normokalemia during the long interdialytic interval, potentially including the relief of associated signs and symptoms and an improved quality of life.
Inclusion Criteria
[0042] For inclusion in the study patients should fulfil the following criteria:
1. Provision of informed consent prior to any study specific procedures.
2. Female or male aged >18 years at screening Visit 1. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
3. Receiving hemodialysis (or hemodiafiltration) three times a week for treatment of endstage renal disease (ESRD) for at least three months before randomization.
4. Patients must have hemodialysis access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter which is expected to remain in place for the entire duration of the study.
5. Pre-dialysis S-K>5.4 mmol/L after long inter-dialytic interval and >5.0 mmol/L after one short inter-dialytic interval during screening.
6. Prescribed dialysate K concentration ≤3 mmol/L during screening
7. Sustained Qb≥200 ml/min and spKt/V≥1.2 (or URR≥63) on stable hemodialysis/hemodiafiltration prescription during screening with prescription (time, dialyzer, blood flow [Qb], dialysate flow rate [Qd] and bicarbonate concentration) expected to remain unchanged during study.
8. Heparin dose (if used) must be stable during screening and expected to be stable during the study.
9. Subjects must be receiving dietary counseling appropriate for ESRD patients treated with hemodialysis/hemodiafiltration as per local guidelines, which includes dietary potassium restriction.
Exclusion Criteria
[0043] Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study.
2. Hemoglobin <9 g/dL on screening (as assessed on Visit 1).
3. Lack of compliance with hemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required).
4. Patients treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 days before screening or anticipated in requiring any of these agents during the study.
5. Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to randomization.
6. Laboratory diagnosis of hypokalemia (S-K<3.5 mmol/L), hypocalcemia (Ca<8.2 mg/dL; for Japan hypocalcemia is defined as albumin-corrected Ca<8.0 mg/dL), hypomagnesemia (Mg<1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the four weeks preceding randomization.
7. Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable).
8. Severe leukocytosis (>20×109/L) or thrombocytosis (>450×109/L) during screening.
9. Polycythemia (Hb>14 g/dL) during screening.
10. Diagnosis of rhabdomyolysis during the four weeks preceding randomization.
11. Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within seven days prior to the first dose of study drug.
12. Patients unable to take oral SZC drug mix.
13. Scheduled date for living donor kidney transplant.
14. Patients with a life expectancy of less than six months.
15. Female patients who are pregnant or breastfeeding.
16. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
17. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof 18. Participation in another clinical study with an investigational product during the last one month before screening.
19. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation.
20. Presence of cardiac arrhythmias or conduction defects that require immediate treatment.
21. History of alcohol or drug abuse within two years prior to randomization.
22. Previous randomization in the present study.
Efficacy Assessments
Serum Potassium Measurements
[0044] Serum potassium levels (S-K) will be measured using i-STAT device (Point-Of-Care analyser) and central laboratory (c-Lab).
Potassium samples will be analysed locally using i-STAT devices for the purpose of dose titration and treatment control. In the event that hemolysis or other artefacts are suspected based on the reported i-STAT result the sample may be re-drawn to confirm the result.
Dialysate Potassium Concentration Prescription and Potassium Levels
[0045] For pre-dialysis serum potassium concentrations <4 mmol/L, subsequent adjustments will be made in accordance to locally accepted clinical practice patterns and guided by the investigator's clinical judgment. For centers that adopt the clinical practice of modifying the prescribed dialysate potassium concentration when the pre-dialysis serum potassium concentration decreases, if pre-dialysis serum K is below 4 mmol/L the dialysate K concentration should be increased by 0.5 or 1 mmol/L according to standard of care, e.g. increase dialysate K from 1K to 1.5 or 2K, from 2K to 2.5 or 3K, or from 3K to 3.5 or 4K.
SZC or placebo will be suspended in 45 ml of water and administered orally on non-dialysis days for a treatment period of eight weeks. The initial SZC dose will be 5 g once daily and may be adjusted to a maximum of 15 g per non-dialysis day to maintain a pre-dialysis S-K between 4-5 mmol/L.
All dose adjustments will be based on pre-dialysis S-K values measured by i-STAT.
Management of dialysis prescription will be according to local clinical pattern practices.
During the first four weeks of the treatment period, the SZC dose should be adjusted if the predialysis potassium value after the long inter-dialytic interval is >5.0 mmol/L (one weekly dose adjustment). For patients taking 5 g on non-dialysis days, the dose should be increased to 10 g on non-dialysis days. For patients taking 10 g, the dose should be increased to 15 g on non-dialysis days. During the first four weeks of the treatment period, both pre- and post-dialysis serum potassium concentrations should be evaluated.
For pre-dialysis serum potassium concentrations <4 mmol/L, subsequent adjustments will be made in accordance to locally accepted clinical practice patterns and guided by the investigator's clinical judgment.
For sites that adopt the clinical practice of modifying the prescribed dialysate potassium concentration when the pre-dialysis serum potassium concentration decreases, if pre-dialysis S-K is below 4 mmol/L the dialysate K concentration should be increased by 0.5 or 1 mmol/L according to standard of care, e.g. increase dialysate K from 1K to 1.5 or 2K, from 2K to 2.5 or 3K, or from 3K to 3.5 or 4K. If dialysate K concentration cannot be increased further (e.g. patient already using 4K dialysate bath), the dose of SZC can be decreased by 5 g or held if the patient is already taking the minimum dose (5 g).
For sites where local clinical practice does not include increasing the dialysate K concentration when pre-dialysis serum K falls, the dose of SZC can be decreased by 5 g or held if the patient is already taking the minimum dose (5 g). If during the treatment phase (initial four weeks) the dose of SZC has been reduced or held and the pre-dialysis potassium value after the next long interdialytic interval is above 5.0 mmol/L, every effort should be made to increase the dose by 5 g or restart SZC 5 g if it was held.
After the first four weeks, no additional adjustments of SZC dose or dialysate potassium concentration should be made unless in the judgement of the principal investigator there is a compelling medical need to treat an abnormal serum potassium concentration, i.e. severe hyperkalemia or hypokalemia with clinical manifestations. If such an event were to occur the appropriate SZC dose adjustment (increase or reduction) can be made with documentation of the event.
In the case of hyperkalemia with clinical manifestations deemed to require urgent treatment, rescue therapy defined as any intervention consistent with local practice patterns to reduce serum K can be administered followed by the appropriate SZC dose adjustment and proper documentation of the event. During the last four weeks of the treatment period, both pre and post-dialysis serum potassium concentrations will continue to be evaluated. It is recommended that the dietary regimen is maintained unchanged during the duration of the study.
Results
[0046] 97 patients were randomised onto SZC and 99 patients were randomized into the placebo group. Except for one patient in the SZC group, all randomized patients received treatment. The primary outcome measure of the study is defined as the proportion of patients who maintain a pre-dialysis serum potassium between 4.0-5.0 mmol/L on 3 out of 4 dialysis treatments following the long interdialytic interval (LIDI), and not receiving rescue therapy, during during the evaluation period (last 4 weeks). The analysis was done using ITT (intention to treat) principle. All randomized patients are in the analysis, even those who did not receive treatment. This means that, for example, difference in treatment discontinuation between treatment arms could have an influence on the result. Even if a patient has missing data, they are included as non-responders (
[0047] The number of patients adverse events was balanced between treatment groups, 40 in the SZC group and 46 in the placebo group. Of these, 7 in the SZC group and 8 in the placebo group were regarded as serious adverse event, including a death in the SZC group, which was judged not to be related to the investigational product. There were 10 patients with pre-dialysis hypokalemia (defined as serum K<3.5 mmol/L, five in each treatment group.
[0048] Pre-dialysis mean serum-K decrease during the dose adjustment period in the SCZ group is stable in the evaluation period and increase after the follow-up period. In the placebo group the pre-dialysis mean serum-K is stable over the treatment period. The post-dialysis mean serum-K shows similar patterns, though less pronounced (
[0049] Mean K-shift is smaller in the SZC group compared to the placebo group starting at visit 9 through the evaluation period. The mean K-shift in the placebo group was about 1.9 mmol/L. The mean K-shift in SZC group was 1.4-1.5 mmol/L between visits 9 and 15.
[0050] Mean K-gradient is smaller in the SZC group compared to the placebo group starting visit 8 through the evaluation period. The mean K-gradient in placebo group was about 3.5 mmol/L. The mean K-gradient in the SZC group was 2.7-2.9 mmol/L between visits 8 to 15.
[0051] The proportion of responders is statistically significantly higher in SZC compared to placebo, with 41.2% responders in the SZC group compared to 1.0% in the placebo group. (