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Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification.
Perelló, Joan; Alberti, Joan; Torres, Juan Vicente; Ferrer, Miguel D; Perez, M Mar; Bassissi, Firas; Gold, Alex; Raggi, Paolo; Chertow, Glenn M; Salcedo, Carolina.
Afiliación
  • Perelló J; Sanifit Therapeutics S.A., Palma, Spain.
  • Alberti J; Department of Chemistry, University of the Balearic Islands, Palma, Spain.
  • Torres JV; ADMETRA Consulting, Palma, Spain.
  • Ferrer MD; Optimapharm, Palma, Spain.
  • Perez MM; Sanifit Therapeutics S.A., Palma, Spain.
  • Bassissi F; Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma, Spain.
  • Gold A; Sanifit Therapeutics S.A., Palma, Spain.
  • Raggi P; Sanifit Therapeutics S.A., Palma, Spain.
  • Chertow GM; Sanifit Therapeutics S.A., Palma, Spain.
  • Salcedo C; Department of Medicine, Stanford University, Palo Alto, CA, United States.
Front Pharmacol ; 15: 1325186, 2024.
Article en En | MEDLINE | ID: mdl-38384289
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 Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax 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 Cmax 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 Cmax ratio of approximately 3 for the doses administered. Average inhibition of hydroxyapatite crystallization was 15%, 61%, and 75%, respectively, and similar across visits. Simple Emax models described 80% maximal effect at exposures >21.9 µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32 µM).

Conclusion:

Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume. Clinical Trial Registration https//www.clinicaltrials.gov; identifier NCT02966028.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Suiza