MO199: A Phase 1, Open-Label, Crossover Study Evaluating The Effect of a Single Dose of Sodium Zirconium Cyclosilicate on the Pharmacokinetics of Tacrolimus and Cyclosporin
Authors: Någård Mats , Choudhury Nurul , Lisovskaja Vera , Mackillop Neil 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Sodium zirconium cyclosilicate (SZC) is a novel, oral, highly selective potassium binder approved for the treatment of hyperkalaemia (HK) in adults. As well as binding potassium, SZC binds hydrogen ions in the acidic environment of the stomach, causing a transient increase in gastric pH which may alter absorption of oral drugs with gastric pH-dependent bioavailability. HK is a recognized issue for renal transplant patients. Tacrolimus and cyclosporin are important drugs in transplant patients, but it is unknown if co-administration of SZC affects their pharmacokinetic (PK) profiles. The aim of this study was to evaluate if the PK profiles of tacrolimus and cyclosporin are altered by SZC co-administration in healthy subjects.

METHOD
This was an open-label, randomized-sequence, 2-cohort crossover study conducted at a site in Germany (NCT04788641). Healthy adults aged 18–50 years were assigned to either cohort 1 (tacrolimus) or cohort 2 (cyclosporin). Subjects in cohort 1 (tacrolimus) received a single dose of tacrolimus 5 mg and tacrolimus 5 mg + SZC 15 g in a random order. Subjects in cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Drug administrations were planned to occur after a 12-h overnight fast and a ≥14-day washout period between treatment periods. Blood samples were collected pre-dose and post-dose up to 72 h. The primary PK endpoints for tacrolimus and cyclosporin were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Secondary endpoints for tacrolimus and cyclosporin were AUC from time zero to the time of the last quantifiable concentration (AUClast), half-life associated with terminal λz of a semi-logarithmic concentration-time curve (t½λz), and time to reach maximum observed concentration (tmax). The difference in mean PK parameters was analysed using a mixed effects model following a natural logarithmic transformation, with period, treatment and sequence as fixed effects, and subject nested within sequence as random effects. Safety and tolerability evaluation included assessment of adverse events (AEs).

RESULTS
Overall, 31 subjects were enrolled in each cohort; 30 subjects in cohort 1 (tacrolimus) and 29 in cohort 2 (cyclosporin) completed the study. Tacrolimus exposure was lower with tacrolimus + SZC compared with tacrolimus alone (Figure 1); Cmax geometric mean ratio (GMR): 71.1% (90% confidence interval [CI] 65.4–77.2), AUCinf: 62.9% (55.6–71.1), AUClast: 65.6% (58.7–73.2). t½λz of tacrolimus was similar between tacrolimus + SZC and tacrolimus alone (GMR: 98.4%; 90% CI 94.6–102.4). Median tmax of tacrolimus was earlier with tacrolimus + SZC (1.50 h) compared with tacrolimus alone (1.75 h; GMR: 83.9%; 90% CI 73.4–95.8).
Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone (Figure 2); Cmax GMR: 102.9% (90% CI 96.1–110.1), AUCinf: 97.2% (92.9–101.7), AUClast: 97.0% (92.7–101.6). t½λz of cyclosporin was comparable with cyclosporin + SZC and cyclosporin alone (GMR: 94.1%; 90% CI 85.7–103.3). Median tmax of cyclosporin was 1.25 h with cyclosporin + SZC and 1.50 h with cyclosporin alone (GMR: 97.6; 90% CI 87.2–109.2).
A total of 15 AEs were reported in 13 subjects with tacrolimus + SZC, 12 AEs in 7 subjects with tacrolimus, 9 AEs in 7 subjects with cyclosporin + SZC and 8 AEs in 8 subjects with cyclosporin. AEs were generally mild in intensity in all groups. There were no serious AEs and no systematic pattern in preferred terms.

CONCLUSION
Tacrolimus exposure was lower when co-administered with SZC 15 g, which has the potential to reduce its immunosuppressive efficacy. As for other oral drugs with drug–drug interactions with SZC, tacrolimus should be administered ≥ 2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.