Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification

Abstract

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52 weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO. Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple E_max model for maximum concentration (C_max) and PD effect, and linear and non-linear E_max models for exposure-efficacy among individual average C_max and absolute and percent changes in CAC score from baseline to week 52. Results: Among evaluable patients receiving placebo (n = 15), 300 mg (n = 20), or 600 mg (n = 20), average C_max across visits was not quantifiable (<0.76 μM), 15 μM, and 46 μM, respectively. These results suggest a more-than-proportional increase, without accumulation, with a C_max ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple E_max models described 80% maximal effect at exposures >21.9 µM and a plateau in exposure-efficacy above the third quartile of C_max (≥32 µM). Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple E_max models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration: https://www.clinicaltrials.gov; identifier NCT02966028.

Keywords: SNF472; calcification; cardiovascular; hexasodium fytate; pharmacodynamics; pharmacokinetics.

FIGURE 1

Patient disposition and analysis sets.

FIGURE 2

Pharmacokinetics and Pharmacodynamics. (A) Hexasodium Fytate Maximum Plasma Concentration (C_max). Average C_max was significantly different between each hexasodium fytate group and placebo (p < 0.001); C_max values by visit were not significantly different within each treatment group (p = 0.631). (B) Mean Inhibition of Calcium-Phosphate (Hydroxyapatite) Crystallization. The average PD effect was significantly different between each hexasodium fytate treatment group and placebo (p < 0.001); the PD effect by visit was not significantly different within each treatment group (p = 0.652).

FIGURE 3

Final PK/PD Model for the Relation Between Average Hexasodium Fytate Maximum Concentration (C_max) and Average Inhibition of Hydroxyapatite Crystallization (% PD inhibition). Black points and lines: mean (±SE) for % PD inhibition by C_max quartile. Box plots for C_max: diamond represents the arithmetic mean, vertical line represents the median, central rectangle spans the first quartile to the third quartile (the interquartile range), and whiskers show the locations of the minimum and maximum.

FIGURE 4

Simple E_max Model for the Relation of Average C_max Over 52 Weeks on Percentage Change from Baseline in Coronary Artery Calcium (CFB CAC) Volume (Back-transformed Values): (A) Individual Values; (B) Mean Values (±SE). Values in parentheses are (quartile average C_max, %CFB CAC). Box Plot display: diamond represents the arithmetic mean, vertical line represents the median, central rectangle spans the first quartile to the third quartile (the interquartile range), and whiskers show the locations of the minimum and maximum.