Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification
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 pro...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1325186/full |
| _version_ | 1797320561809948672 |
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| author | Joan Perelló Joan Perelló Joan Alberti Juan Vicente Torres Miguel D. Ferrer Miguel D. Ferrer M. Mar Perez Firas Bassissi Alex Gold Alex Gold Paolo Raggi Glenn M. Chertow Carolina Salcedo |
| author_facet | Joan Perelló Joan Perelló Joan Alberti Juan Vicente Torres Miguel D. Ferrer Miguel D. Ferrer M. Mar Perez Firas Bassissi Alex Gold Alex Gold Paolo Raggi Glenn M. Chertow Carolina Salcedo |
| author_sort | Joan Perelló |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T04:44:49Z |
| format | Article |
| id | doaj.art-7ccee23001fc4160a0848c9318babc57 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T04:44:49Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-7ccee23001fc4160a0848c9318babc572024-02-08T11:07:22ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-02-011510.3389/fphar.2024.13251861325186Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcificationJoan Perelló0Joan Perelló1Joan Alberti2Juan Vicente Torres3Miguel D. Ferrer4Miguel D. Ferrer5M. Mar Perez6Firas Bassissi7Alex Gold8Alex Gold9Paolo Raggi10Glenn M. Chertow11Carolina Salcedo12Sanifit Therapeutics S.A., Palma, SpainDepartment of Chemistry, University of the Balearic Islands, Palma, SpainADMETRA Consulting, Palma, SpainOptimapharm, Palma, SpainSanifit Therapeutics S.A., Palma, SpainDepartment of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma, SpainSanifit Therapeutics S.A., Palma, SpainSanifit Therapeutics S.A., Palma, SpainSanifit Therapeutics S.A., Palma, SpainDepartment of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, CanadaDepartment of Medicine, Stanford University, Palo Alto, CA, United StatesSanifit Therapeutics S.A., Palma, SpainBackground: 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.https://www.frontiersin.org/articles/10.3389/fphar.2024.1325186/fullpharmacokineticspharmacodynamicshexasodium fytateSNF472calcificationcardiovascular |
| spellingShingle | Joan Perelló Joan Perelló Joan Alberti Juan Vicente Torres Miguel D. Ferrer Miguel D. Ferrer M. Mar Perez Firas Bassissi Alex Gold Alex Gold Paolo Raggi Glenn M. Chertow Carolina Salcedo Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification Frontiers in Pharmacology pharmacokinetics pharmacodynamics hexasodium fytate SNF472 calcification cardiovascular |
| title | Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification |
| title_full | Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification |
| title_fullStr | Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification |
| title_full_unstemmed | Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification |
| title_short | Hexasodium fytate exposure-response correlations in a randomized, placebo-controlled study of patients on dialysis with cardiovascular calcification |
| title_sort | hexasodium fytate exposure response correlations in a randomized placebo controlled study of patients on dialysis with cardiovascular calcification |
| topic | pharmacokinetics pharmacodynamics hexasodium fytate SNF472 calcification cardiovascular |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1325186/full |
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