Evaluation of potential drug interactions with sodium zirconium cyclosilicate: a single-center, open-label, one sequence crossover study in healthy adults

Abstract

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is an oral potassium binder for the treatment of hyperkalemia in adults. SZC acts in the gastrointestinal tract and additionally binds hydrogen ions in acidic environments like the stomach, potentially transiently increasing gastric pH and leading to drug interactions with pH-sensitive drugs. This study assessed potential pharmacokinetic (PK) interactions between SZC and nine pH-sensitive drugs.

Methods: In this single-dose, open-label, single-sequence cross-over study in healthy adults, amlodipine, atorvastatin, clopidogrel, dabigatran, furosemide, glipizide, levothyroxine, losartan or warfarin were each administered alone and, following a washout interval, with SZC 10 g. Maximum plasma concentration (C _max), area under the plasma concentration-time curve from 0 to the last time point (AUC_{0- t} ) and AUC extrapolated to infinity (AUC_inf) were evaluated. No interaction was concluded if the 90% confidence interval for the geometric mean ratio (SZC coadministration versus alone) of the PK parameters was within 80-125%.

Results: During SZC coadministration, all PK parameters for amlodipine, glipizide, levothyroxine and losartan showed no interaction, while reductions in clopidogrel and dabigatran C _max, AUC_{0- t} and AUC_inf (basic drugs) were <50% and increases in atorvastatin, furosemide and warfarin C _max (acidic drugs) exceeded the no-interaction range by ˂2-fold.

Conclusions: SZC coadministration was associated with small changes in plasma concentration and exposure of five of the nine drugs evaluated in this study. These PK drug interactions are consistent with transient increases in gastric pH with SZC and are unlikely to be clinically meaningful.

Keywords: drug interactions; gastric pH-sensitive drugs; hyperkalemia; pharmacokinetic analysis; sodium zirconium cyclosilicate.

FIGURE 1:

Study design. ^aThe washout interval was 7 days for the clopidogrel, dabigatran, glipizide, losartan and furosemide cohorts; 14 days for the atorvastatin, amlodipine and warfarin cohorts; and 35 days for the levothyroxine cohort.

FIGURE 2:

Participant disposition. ^aOne participant from the amlodipine cohort was lost to follow-up during dosing period 1. ^bOne participant from the amlodipine cohort was unable to return on the final day of dosing period 2 and discontinued on Day 8. ^cTwo participants from the levothyroxine cohort who were unable to return for dosing period 2 were excluded based on the sponsor’s decision during the washout interval.

FIGURE 3:

Forest plot of the least-squares GMR (90% CI) for SZC + drug versus drug alone. Dark shading indicates strict no-interaction criteria (90% CI of GMR within 80–125%), medium shading indicates 90% CI up to 150% and light shading indicates 90% CI up to 200%. AUC_0–t, area under the plasma concentration-time curve from 0 to the final time with a concentration ≥LLOQ; AUC_inf, area under the plasma concentration-time curve extrapolated to infinity.

FIGURE 4:

Plasma concentration-time curves for (A) atorvastatin, (B) o-OH atorvastatin, (C) p-OH atorvastatin, (D) clopidogrel, (E) clopidogrel acid, (F) dabigatran, (G) furosemide, (H) R-warfarin and (I) S-warfarin with and without SZC coadministration.