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

Abstract

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 (AUC_0-∞), and maximum concentration ( C_max). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC_0-∞ and C_max 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 AUC_0-∞ remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC_0-∞ 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 AUC_0-∞ was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for C_max 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 AUC_0-∞ and C_max 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.

Keywords: absorption; dose separation; drug–drug interactions; hyperkalemia; patiromer; potassium-binder.

Figure 1.

Design of in vivo drug interaction studies: open-label, randomized, 3-way crossover. Treatment A—Each victim drug was administered alone within 30 minutes after the start of a standard breakfast (day 1), except for levothyroxine administered within 40 minutes before breakfast. Treatment B—Victim drugs were administered together with patiromer. Each victim drug was given within 30 minutes after the start of a standard breakfast and patiromer within 10 minutes after the victim drug (day 1), except levothyroxine, administered at 40 minutes before breakfast followed by patiromer administered with breakfast. Treatment C—Victim drugs were administered between 2 patiromer doses. The first dose of patiromer was administered within 30 minutes after the start of a standard lunch (day −1). Each of the victim drugs was administered 21 hours after the first patiromer dose and within 30 minutes of a standard breakfast on day 1 (except levothyroxine, which was administered at 40 minutes prior to standard breakfast). The second patiromer dose was administered 3 hours after the victim drug and within 30 minutes after the start of a standard lunch. ^aPatiromer and the victim drugs were always administered with meals, except for levothyroxine, which was given on empty stomach, within 40 minutes prior to the meal. ^bDuration from administration of victim drug to final draw of blood for pharmacokinetics (PK) analysis of drug concentration varied, generally depending on the PK characteristics of the victim drug. Time from the administration of victim drug (day 0) to the beginning of washout (hours): warfarin (168); verapamil (36), lithium (96), trimethoprim (60), amlodipine (144), cinacalcet (144), furosemide (12), metoprolol (36), clopidogrel (32), ciprofloxacin (24), metformin (24), and levothyroxine (48). ^cDuration of washout before the administration of victim drug after crossover from previous treatment varied, depending on the PK characteristics of the drug. Between-treatment washout periods (in days): warfarin (≥19), verapamil (≥5), lithium (≥10), trimethoprim (≥4), amlodipine (≥14), cinacalcet (≥10), furosemide (≥4), metoprolol (≥5), clopidogrel (≥3), ciprofloxacin (≥3), metformin (≥4), and levothyroxine (≥35).

Figure 2.

Subject disposition.

Figure 3.

Forest plot of geometric mean ratios (victim/patiromer). A and B, Patiromer administered together with a victim drug: (A) AUC_0-∞ and (B) C _max. C and D, Victim drugs administered 21 hours after the first patiromer dose and 3 hours before the second patiromer dose: (C) AUC_0-∞ and (D) C _max. Patiromer and all victim drugs were always administered with food, except for levothyroxine which is recommended to be administered 1/2 to 1 hour before breakfast on an empty stomach. Consequently, patiromer and levothyroxine were not administered at the same time and “administered together” represents a 40-minute separation between levothyroxine and patiromer. ^aValues adjusted for baseline thyroxine concentration, AUC for 48-hour sampling profile (AUC_0-48) is shown because extrapolation to infinity is not valid for levothyroxine due to endogenous thyroxine production. AUC_0-48 indicates area under the plasma concentration time curve from time 0 to 48 hours; AUC_0-∞, area under the plasma concentration time curve from time 0 extrapolated to infinity; C _max, maximum observed plasma concentration; LCL, lower confidence interval limit; N, enrolled subjects; UCL, upper confidence interval limit.

Figure 4.

Flowchart of drugs tested in and results of in vitro binding and in vivo drug–drug interaction studies.