It works by binding potassium in the intestine.
The active moiety of patiromer for oral suspension is an unabsorbed polymer that binds potassium in exchange for calcium, predominantly in the distal colon. The concentration of free potassium is higher, increasing fecal potassium excretion and decreasing levels. Serum potassium.
Patiromer is used to treat hyperkalemia, but not as an emergency treatment for life-threatening hyperkalemia, as it acts relatively slowly.
Such a condition necessitates other types of treatment, for example, calcium infusions, insulin plus glucose infusions, salbutamol inhalation, and hemodialysis.
Typical reasons for hyperkalemia are kidney failure and medications that inhibit the renin-angiotensin-aldosterone system (RAAS).
Also, ACE inhibitors, angiotensin II receptor antagonists or potassium-sparing diuretics, or those that interfere with kidney function in general, such as non-steroidal anti-inflammatory drugs (NSAIDs).
Hyperkalemia, also called hyperkalemia, is an elevated potassium (K +) level in the blood serum. Normal potassium levels are between 3.5 and 5.0 mmol / L (3.5 and 5.0 mEq / L) with levels above 5.5 mmol / L defined as hyperkalemia.
Usually, this does not produce symptoms. Occasionally, it causes palpitations, muscle pain, muscle weakness, or numbness when severe. An abnormal heart rate can lead to cardiac arrest and death.
Common causes include kidney failure, hypoaldosteronism, and rhabdomyolysis. Several medications can also cause high blood potassium, such as spironolactone, non-steroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors.
Severity is divided into mild (5.5–5.9 mmol / L), moderate (6.0–6.4 mmol / L), and severe (> 6.5 mmol / L).
High levels can also be detected on an electrocardiogram (ECG). Pseudohyperkalemia, due to the breakdown of cells during or after taking the blood sample, should be ruled out.
The initial treatment in those with changes in the electrocardiogram is calcium gluconate. Medications that could worsen the disease should be stopped, and a low potassium diet is recommended.
Other medications used include dextrose with insulin, salbutamol, and sodium bicarbonate. Measures to remove potassium from the body include furosemide, polystyrene sulfonate, and hemodialysis.
Hemodialysis is the most effective method. The use of polystyrene sulfonate, while joint, is poorly supported by the evidence.
Hyperkalemia is rare in healthy people. Among those in the hospital, the rates are between 1% and 2.5%. It increases the overall risk of death by at least tenfold.
The word “hyperkalemia” comes from hyper-high meaning; kalium means potassium; and -Emma, which means “in the blood.”
Patiromer was generally well tolerated in the studies.
The side effects that occurred in more than 2% of the patients included in clinical trials were mainly gastrointestinal problems such as:
- Constipation, diarrhea, nausea and flatulence, and hypomagnesemia (low magnesium levels in the blood) in 5% of patients because the patiromer binds to magnesium in the intestine.
Safety and tolerability were reported in studies.
Overall, 51 of 113 evaluable safety patients had at least one AE during the study (24 in the no-food group and 27 in the food group).
The most common adverse events (occurring in ≥3 patients in total); included mild diarrhea in 3 patients, each in the groups without food and with food, mild to moderate constipation in 2 patients in each group, and a slight increase in creatine phosphokinase in 1 and 3 patients.
Adverse events considered by the investigators related to patiromer were reported in 13 patients; the most common class of treatment-related adverse events were gastrointestinal, occurring in 7 patients overall.
Four patients had five non-fatal serious adverse events, none of which the investigators considered related to patiromer.
These included two adverse events of angina pectoris in one patient in the food group and acute kidney injury in one patient in the no food group; both patients were discontinued from the study.
Two other patients in the no-food group had severe adverse events that did not lead to discontinuation of patiromer administration: intermittent claudication in one patient that resolved with treatment and anemia in another patient that resolved without treatment.
One death was reported; the patient in the group without food died on day 9 of the study from a cardiopulmonary arrest that the researcher considered was not related to the heteromeric treatment.
The patient had had type 2 diabetes mellitus, hypertension, and hypercholesterolemia and had not attended the scheduled study visit for week one due to hypoglycemia.
Serum potassium measured at the last visit before death (day 3) was 5.1 mEq / L, down from 5.4 mEq / L at the start of the study.
The safety review board evaluated death as the cardiovascular cause (sudden cardiac death) and is unlikely to be related to hypokalaemia or hyperkalemia.
Patiromer was tested for drug interactions with 28 drugs and showed binding or exchange with 14 pills.
This could reduce its availability and, therefore, its effectiveness, so patiromer has received a warning from the US Food and Drug Administration (FDA), which tells patients who wait at least six hours between taking patiromer and any other oral medication.
Of the 14 drugs that showed interaction in vitro, 12 were selected for further testing in phase 1 studies in healthy volunteers to assess whether the results observed in vitro translated into an effect in people.
These studies showed that the patiromer did not alter the absorption of nine of the 12 drugs when co-administered.
Patiromer reduced the absorption of three drugs when co-administered. However, there was no interaction when patiromer was administered, and these three drugs were taken 3 hours apart.
This information was submitted to the Food and Drug Administration in the form of a new Supplemental Drug Application (sNDA).
And as a result, in November 2016, the Food and Drug Administration approved the removal of the boxed warning about the separation of patiromer and other oral medications.
The updated label recommends that patients take Patiromer at least 3 hours before or 3 hours after other oral medications.
Mechanism of action
Patiromer works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange, thereby reducing the amount of potassium available for absorption into the bloodstream and increasing the amount excreted through the stool.
The net effect is a reduction in potassium levels in the blood serum. The decrease in potassium levels is detectable 7 hours after administration.
If treatment continues, levels decline for at least 48 hours and remain stable for 24 hours after the last dose is administered. After this, potassium levels rise again over at least four days.
The patiromer is not absorbed from the intestine; it is not metabolized and is excreted unchanged with the feces.
The substance is a cross-linked polymer of 2-fluoro acrylic acid (91% in terms of the amount of substance) with divinylbenzenes (8%) and 1,7-octadiene (1%).
It is used in the form of its calcium salt (2: 1 ratio) and with sorbitol (one molecule for two calcium ions or four units of fluoro acrylic acid), a combination called patyromer sorbitex calcium.
Patiromer Sorbitex Calcium is an off-white to light brown, free-flowing amorphous powder. It is insoluble in water, 0.1M hydrochloric acid, heptane, and methanol.
In a multicenter phase III clinical trial that enrolled 237 hyperkalemic patients on treatment with renin-angiotensin-aldosterone system inhibitors, 76% of participants achieved normal serum potassium levels within four weeks.
After subsequent randomization of 107 responders into a group that received continuous patyromeric treatment and a placebo group, the reappearance of hyperkalemia was 15% versus 60%, respectively.
The US Food and Drug Administration approved the patyromer in October 2015. The drug is now also supported in Europe as of July 2017.
Dosage forms and strengths
Oral powder for suspension
- 4g / pack.
- 8g / pack.
- 2g / pack.
Patiromer is not indicated for acute and life-threatening hyperkalemia due to its slower action.
The dosing patiromer is available in 8.4 g, 16.8 g, or 25.5 g single-use packages. The recommended dose is 8.4 g per day, titrated weekly by 8.4 g to reach the desired potassium level, up to 25.2 g per day.
Patiromer should be taken with food in its reconstituted form and should not be dry, heated, or mixed with any wild food or liquid. Patients should follow the manufacturer’s recommended preparation instructions.
Dose adjustments are not required in renal failure. The patiromer must be refrigerated; If stored at room temperature, it should be used within three months.
Patiromer is equally effective and well-tolerated when taken without food or with food, thus offering the potential for dosage flexibility.
Studies of the drug patiromer
In October, the Food and Drug Administration approved patiromer (Veltassa; Relypsa) to treat the patients.
The patiromer is an oral potassium binder that is not absorbed systemically. It functions as a cation exchange polymer with calcium as a counter ion, leading to the fecal excretion of potassium.
Patiromer and Hyperkalemia
A phase III trial (OPAL-HK) studied the patiromer in patients with stage 3 or 4 chronic kidney disease (CKD) who took a stable dose of at least one renin-angiotensin-aldosterone system inhibitor and had serum potassium of 5.1 to <6.5 mmol / L at screening.
A four-week single-blind and single-blind treatment phase allowed patiromer treatment to be administered at 4.2g or 8.4g twice daily, depending on potassium levels.
Those with a potassium of 5.5 mmol / L or more at the beginning of the study and between 3.8 and <5.1 mmol / L at the end of the acute phase were randomized to continue their dose or receive a placebo in an 8-week double-blind study.
Two hundred forty-three patients were treated in the acute phase, the majority (62.1%) with moderate to severe hyperkalemia.
The mean change in potassium from baseline to week four was -1.01 mmol / L (95% CI, -1.07 to -0.95), with a more significant difference seen in those with a higher baseline potassium level.
Seventy-six percent of patients achieved target potassium of 3.8 to <5.1 mmol / L at the end of the acute phase, with an average daily dose of 12.8 g and 21.4 g in those with mild and moderate to severe hyperkalemia, respectively.
A total of 107 patients were randomized to the abstinence phase, where a difference in potassium change between those randomized to patiromer versus placebo was found to be 0.72 mmol / L (0.46 to 0, 99).
The time to the first hyperkalemic recurrence was prolonged in those who continued with patiromer.
At the end of the withdrawal phase, most patients in the pyrometric group (94%) continued their therapy of the renin-angiotensin-aldosterone system, as opposed to 44% in the placebo group.
The long-term efficacy of the patiromer was demonstrated in a 52-week open-label study (AMETHYST-DN) in patients with chronic kidney disease and type 2 diabetes mellitus, in whom optimization of antihypertensive therapy was indicated.
Patients were managed with combinations of losartan and spironolactone, and those who developed hyperkalemia during this initial phase were randomly assigned to one of six patyromeric treatment groups, stratified by baseline potassium levels.
-Doses were adjusted to target potassium of 5.0 mEq / L or less. At week four, potassium levels decreased in all patiromer groups and were maintained for 52 weeks.
In PEARL-HF, the use of patiromers resulted in a significant decrease in potassium, a lower incidence of hyperkalemia, and a more frequent achievement of the 50 mg daily dose of spironolactone compared to placebo in normokalemic patients with heart failure who began to take spironolactone.
Long-term data from the AMETHYST-DN trial indicate that the most common treatment-related adverse events include hypomagnesemia, mild or moderate constipation, diarrhea, hypomagnesemia, nausea, abdominal discomfort, or flatulence.
The drug label suggests magnesium monitoring in patients taking patiromer and magnesium supplements if necessary. Patiromer is contraindicated in patients with hypersensitivity to the drug.
The binding of patiromer with other orally administered medications may decrease its absorption and efficacy. Therefore the administration of other oral medications should occur six hours before or after the patiromer dose.
In addition, patyromer treatment should be avoided in patients with severe constipation, intestinal obstruction, or impaction, as the gastrointestinal condition may be worsened by patyromer treatment.
Patiromer and kidney disease
Among patients with chronic kidney disease taking inhibitors of the renin-angiotensin-aldosterone system, patiromer treatment was associated with a reduction from baseline in elevated serum potassium levels.
Subsequently, normokalemia was maintained more effectively than in patients who received a placebo. The incidence of hypokalemia was low, there were few gastrointestinal side effects, and the patiromer dose had to be adjusted infrequently.
Patients in whom persistent or sustained hyperkalemia develops often have multiple risk factors. The most important of which are chronic kidney disease and diabetes and the concomitant use of inhibitors of the renin-angiotensin-aldosterone system.
Approximately 85% of the patients had an eGFR of 15 to less than 60 ml per minute per 1.73 m2; all were receiving inhibitors of the renin-angiotensin-aldosterone system, and substantial proportions had hypertension, diabetes, heart failure, or coronary artery disease.
Therefore, the study population was representative of patients who generally benefit from therapy with renin-angiotensin-aldosterone system inhibitors.
A range of elevated serum potassium levels (5.1 to <6.5 mmol per liter) was used to qualify patients for inclusion in the study, with 62% of patients having a baseline potassium level of 5.5 mmol per liter or more.
A finding represents the wide range of potassium elevations seen in patients with chronic kidney disease and hyperkalemia taking inhibitors of the renin-angiotensin-aldosterone system.
Overall, 76% of qualified hyperkalemic patients treated with patiromer in the initial treatment phase had normal potassium levels at week 4.
Among patients with moderate to severe hyperkalemia, the mean potassium level was less than 5.5 mmol per liter 2 days after treatment, which was the time of the first post-baseline assessment.
A serum potassium level of 5.5 mmol per liter is the threshold at which many clinicians initiate strategies to control hyperkalemia.
Among patients with mild hyperkalemia, mean potassium levels decreased to less than 5.1 mmol per liter after two days of treatment.
In the random withdrawal phase, the incidence of recurrent hyperkalemia (when defined as a potassium level ≥5.5 mmol per liter) was four times higher than in the patiromer group (60% vs. 15% ), with recurrent hyperkalemia more rapidly in the placebo group.
Almost four times more patients in the placebo group than in the pyrometric group required an intervention to lower their potassium level.
In 56% of patients in the placebo group, compared with 6% of patients in the pyrometric group, discontinuation of renin-angiotensin-aldosterone system inhibitors was required to control serum potassium levels adequately.
Mild to moderate constipation, the most common adverse event with patiromer (occurring in 11% of patients during the initial treatment phase and 4% during the random withdrawal phase), generally did not limit treatment.
Rates of all other adverse events with patiromer were low and similar to placebo in the randomized withdrawal phase.
Few serious adverse events occurred; the investigators, aware of the treatment assignments, did not attribute any of these events to patiromer.
Hypokalemia was rare and reversible, suggesting it can be mitigated by monitoring serum potassium levels and adjusting the patiromer dose.
Although this study showed the benefit of the patiromer in treating hyperkalemia.
And in reducing the risk of recurrence and also showed that more patients in the patiromer group than in the placebo group were able to continue taking inhibitors of the renin-angiotensin-aldosterone system.
Additional data evaluating the patiromer requires long-term therapy (> 12 weeks).
None of the trial phases was double-blind; however, the phlebotomy staff, medical monitors, and patients were unaware of group assignments during both stages.
And the statistical staff, members of the central EKG laboratory, and the safety review board were unaware of group assignments during the random withdrawal phase.
Since patients with serum potassium levels of 6.5 mmol per liter were enrolled in the initial treatment phase, the placebo control was considered unethical.
The use of an active control (i.e., sodium or calcium polystyrene sulfonate) was not considered clinically appropriate due to the lack of perspective. It controlled data on these agents, their potential to cause intestinal necrosis, and the absence of a standard of care. For use beyond the acute setting.