Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease.

AIMS: Hyperkalaemia risk precludes optimal renin-angiotensin-aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+ )-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone. METHODS AND RESULTS: This open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3-5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0-5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48-4.70 mEq/L during treatment. Serum K+ of 3.5-5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0-5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients]. CONCLUSIONS: In this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.

Serum-to-dialysate potassium gradient and its association with short-term outcomes in hemodialysis patients.

Background: A high serum-to-dialysate potassium (K+) gradient at the start of dialysis leads to rapid lowering of serum K+ and may confer a greater risk of adverse events. Here, we examined the near-term association of K+ gradient with clinical outcomes. Methods: This retrospective (2010-11) event-based study considered 830 741 patient-intervals, each defined by a pre-dialysis measurement of serum K+ made among adult Medicare Parts A and B enrollees who received in-center hemodialysis on a Monday/Wednesday/Friday schedule at a large US dialysis organization. K+ gradient was considered based on the difference in K+ concentration (serum-dialysate) on the date of measurement; analyses accounted for multiple observations per patient. Outcomes considered were: all-cause and cardiovascular hospital admissions, emergency department (ED) visits and deaths. Results: Higher K+ gradient was associated with younger age, greater fistula use, lower comorbidity scores and better nutritional indices. Adjusting for patient differences, there was a dose-response relationship between higher K+ gradient and greater risks of all-cause hospitalization and ED visit. A similar trend was seen for cardiovascular hospitalization but did not achieve statistical significance. No associations were observed with mortality, potentially due to a low number of events. Conclusions: Higher K+ gradient is independently associated with greater risk of all-cause hospitalizations and ED visits. Further research is needed to determine whether interventions that reduce the K+ gradient ameliorate this risk.

Evaluation of the Potential for Drug Interactions With Patiromer in Healthy Volunteers.

INTRODUCTION: Patiromer is a potassium-binding polymer that is not systemically absorbed; however, it may bind coadministered oral drugs in the gastrointestinal tract, potentially reducing their absorption. METHODS: Twelve randomized, open-label, 3-period, 3-sequence crossover studies were conducted in healthy volunteers to evaluate the effect of patiromer (perpetrator drug) on absorption and single-dose pharmacokinetics (PK) of drugs (victims) that might be commonly used with patiromer. Subjects received victim drug alone, victim drug administered together with patiromer 25.2 g (highest approved dose), and victim drug administered 3 hours before patiromer 25.2 g. The primary PK endpoints were area under the curve (AUC), extrapolated to infinity (AUC0-∞), and maximum concentration ( Cmax). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC0-∞ and Cmax ratios with prespecified equivalence limits of 80% to 125%. RESULTS: Overall, 370 subjects were enrolled, with 365 receiving ≥1 dose of patiromer; 351 subjects completed the studies and all required treatments. When coadministered with patiromer, the 90% CIs for AUC0-∞ remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC0-∞ point estimate ratios for levothyroxine and metformin with patiromer coadministration were ≥80%, with the lower bounds of the 90% CIs at 76.8% and 72.8%, respectively. For ciprofloxacin, the point estimate for AUC0-∞ was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for Cmax were ≥80% with patiromer coadministration; for ciprofloxacin, clopidogrel, metformin, and metoprolol, the point estimates were <80%. When patiromer was administered 3 hours after each victim drug, the 90% CIs for AUC0-∞ and Cmax for each drug were within the prespecified 80% to 125% limits. CONCLUSION: For 9 of the 12 drugs coadministered with patiromer, there were no clinically significant drug-drug interactions. For 3 drugs (ciprofloxacin, levothyroxine, and metformin), a 3-hour separation between patiromer and their administration resulted in no clinically significant drug-drug interactions.

Serum Potassium and Short-term Clinical Outcomes Among Hemodialysis Patients: Impact of the Long Interdialytic Interval.

BACKGROUND: Hyperkalemia is common among hemodialysis patients and is associated with morbidity and mortality. The long interdialytic interval is likewise associated with adverse outcomes. However, the interplay among serum potassium, dialysis cycle phase, and clinical outcomes has not been examined. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: 52,734 patients receiving in-center hemodialysis at a large dialysis organization during 2010 and 2011 contributed 533,889 potassium measurements (230,634 on Monday; 285,522 on Wednesday; 17,733 on Friday). PREDICTOR: Serum potassium concentration, day of the week of potassium measurement. OUTCOMES: Death, hospitalization, emergency department (ED) visit. RESULTS: There was a significant association between higher serum potassium and risk of hospitalization within 96 hours that was of greater magnitude on Fridays (389 hospitalizations) than Mondays or Wednesdays (4,582 and 4,629 hospitalizations, respectively; P for interaction = 0.008). Serum potassium of 5.5 to <6.0 (vs the referent category of 4.0-<4.5 mEq/L) was associated with increased risk of hospitalization on Fridays, with an adjusted OR of 1.68 (95% CI, 1.22-2.30). However, serum potassium of 5.5 to <6.0 mEq/L was associated with only mild elevation of risk on Mondays and no significantly increased risk on Wednesdays (adjusted ORs of 1.12 [95% CI, 1.00-1.24] and 1.04 [95% CI, 0.94-1.16], respectively). Associations of elevated serum potassium (6.0-<6.5 mEq/L or greater) with death and ED visit were significant, but did not differ based on day of the week. LIMITATIONS: There were insufficient observations to detect effect modification by day of the week for deaths, ED visits, and specific causes of hospitalizations. Confounding may have influenced results. CONCLUSIONS: Higher serum potassium is associated with increased short-term risk of hospitalization, ED visit, and death. The association between serum potassium and hospitalization risk is modified by day of the week, consistent with a contribution of accumulated potassium to adverse outcomes following the long interdialytic interval. Further work is needed to determine whether directed interventions ameliorate this risk.

Effect of Patiromer on Urinary Ion Excretion in Healthy Adults.

BACKGROUND AND OBJECTIVES: Patiromer is a nonabsorbed potassium-binding polymer that uses calcium as the counterexchange ion. The calcium released with potassium binding has the potential to be absorbed or bind phosphate. Because binding is not specific for potassium, patiromer can bind other cations. Here, we evaluate the effect of patiromer on urine ion excretion in healthy adults, which reflects gastrointestinal ion absorption. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed the effect of patiromer on urine potassium, sodium, magnesium, calcium, and phosphate in two studies. Healthy adults on controlled diets in a clinical research unit were given patiromer up to 50.4 g/d divided three times a day for 8 days (dose-finding study) or 25.2 g/d in a crossover design as daily or divided (two or three times a day) doses for 18 days (dosing regimen study). On the basis of 24-hour collections, urinary ion excretion during the baseline period (days 5-11) was compared with that during the treatment period (days 13-19; dose-finding study), and the last 4 days of each period were compared across regimens (dosing regimen study). RESULTS: In the dose-finding study, patiromer induced a dose-dependent decrease in urine potassium, urine magnesium, and urine sodium (P<0.01 for each). Patiromer at 25.2 g/d decreased urine potassium (mean±SD) by 1140±316 mg/d, urine magnesium by 45±1 mg/d, and urine sodium by 225±145 mg/d. Urine calcium increased in a dose-dependent manner, and urine phosphate decreased in parallel (both P<0.01). Patiromer at 25.2 g/d increased urine calcium by 73±23 mg/d and decreased urine phosphate by 64±40 mg/d. Urine potassium, urine sodium, and urine magnesium were unaffected by dosing regimen, whereas the increase in urine calcium was significantly lower with daily compared with three times a day dosing (P=0.01). Urine phosphate also decreased less with daily compared with two or three times a day dosing (P<0.05). CONCLUSIONS: In healthy adults, patiromer reduces urine potassium, urine sodium, urine magnesium, and urine phosphate, while modestly increasing urine calcium. Compared with divided dosing, administration of patiromer once daily provides equivalent reductions in urine potassium, urine sodium, and urine magnesium, with less effect on urine calcium and urine phosphate.