A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma

Ferrer, Miguel D.; Pérez, María-Eglée; Cànaves, M. M.; Fuster, Juan Manuel Buades; Salcedo, Carolina; Perelló, Joan

doi:10.1038/s41598-017-07203-x

Cited by 30 publications

(31 citation statements)

References 51 publications

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“…Repeated administration (3 times per week) of SNF472 at 10 mg/kg for 4 weeks does not affect the crystallization inhibitory potential of the compound. The crystallization inhibitory potential of SNF472 is comparable along all cohorts and is in line with previous PD studies evaluating the effects of SNF472 on HAP crystallization, and support the use of SNF472 for the treatment of CVC in HD patients. The design of this Phase 1b trial allowed us to evidence, for the first time, a PK‐PD relationship for SNF472 in HD patients.…”

Section: Discussionsupporting

confidence: 87%

“…The PD of SNF472 administered by IV infusion was evaluated by measuring HAP crystallization . For this purpose, 2 samples from each subject were used for PD analysis: 1 sample obtained at baseline before SNF472 infusion and 1 sample at T max , obtained at the end of the 4 hours of infusion.…”

Section: Methodsmentioning

confidence: 99%

“…It is an intravenous (IV) formulation of myo‐inositol hexaphosphate (IP6). In vitro and in vivo results show that SNF472 or IP6 prevent the formation of hydroxyapatite (HAP) crystals. SNF472 directly inhibits calcium crystal formation by binding to the surface of the crystal, and IV SNF472 administration to HD patients could mitigate the impact of the imbalance between CVC inhibitors and enhancers present in these patients.…”

Section: Introductionmentioning

confidence: 99%

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A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

Salcedo

Joubert

Ferrer

et al. 2019

Brit J Clinical Pharma

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Aims: SNF472 is a calcification inhibitor that is being studied as a novel treatment for calciphylaxis and cardiovascular calcification (CVC). A first study showed acceptable safety and tolerability in a single ascending dose administration in healthy volunteers and a single dose administration in haemodialysis (HD) patients. This study aimed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics relationship of intravenous SNF472 in HD patients in a multiple ascending dose administration trial with 5 doses tested for 1 week (3 administrations) and 1 dose tested for 4 weeks (12 administrations).Methods: This double blind, randomized, placebo-controlled Phase 1b study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of SNF472 after repeated administrations to HD patients for up to 28 days. A pharmacodynamic assessment was performed to evaluate the potential for SNF472 to inhibit hydroxyapatite (HAP) formation. Patients were grouped into 2 cohorts, receiving multiple ascending doses for 1 week (1 to 20 mg/kg, Cohort 1) and 1 dose of 10 mg/kg for 4 weeks (Cohort 2) of intravenous SNF472.Results: Physical status, body weight, cardiorespiratory function, body temperature and laboratory parameters were in the normal range. No clinically relevant effects on heart rate or blood pressure were observed. No abnormal electrocardiogram or QTcB period were reported. The peak plasma concentration (7.6, 16.1, 46.0 and 66.9 μg/mL for 3, 5, 12.5 and 20 mg/kg, respectively) was observed at the end of the 4-hour infusion and thereafter concentrations declined rapidly with half-life between 32 and 65 min. SNF472 at 10 mg/kg inhibited dose dependently HAP crystallization in plasma samples after 28 days of treatment (78% inhibition, P < .001).Conclusions: SNF472 is safe and well tolerated in HD patients after 2 schemes: multiple ascending doses for 1 week and after repeated dosing of 10 mg/kg for 4 weeks. In both schemes, SNF472 inhibits the induction of HAP crystallization.These results provide support for the use of SNF472 as a novel treatment for CVC in end-stage renal disease.The authors confirm that the PI for this paper is Francesc Maduell and that he had direct clinical responsibility for patients.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

Salcedo

Joubert

Ferrer

et al. 2019

Brit J Clinical Pharma

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“…A PD assay to measure the crystallization potential of blood through the artificial induction of calcium phosphate crystal formation in blood samples was validated in human and rat plasma samples [19]. These studies demonstrated that the addition of SNF472 to rat plasma samples ex vivo reduced the HAP crystallization rate (up to 80%), which was comparable to in vivo results that demonstrated a reduction in HAP crystallization potential of plasma by up to 70% following subcutaneous administration of SNF472 to rats.…”

Section: Discussionmentioning

confidence: 67%

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Perelló

Joubert

Ferrer

et al. 2018

Brit J Clinical Pharma

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Aims SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. Methods This is a first‐time‐in‐human, double‐blind, randomized, placebo‐controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. Results Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg–1 and the dose ascended to 12.5 mg kg–1. The dose selected for HD patients was 9 mg kg–1. Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment‐emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg–1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3–84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, –32.4 to 49.7). Conclusion The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end‐stage renal disease and calciphylaxis warranting further human studies.

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“…Furthermore, the accumulation of fetuin-A-containing mineral particles was noted in the peritoneal dialysate of a patient suffering from calcifying peritonitis [10] and in patients suffering from chronic kidney disease (CKD) [11]. Recent work has shown that both the abundance of CPP [12][13][14] and the kinetics of CPP formation [15][16][17][18] in serum of CKD patients can be used to monitor the calcification propensity of these patients. The function of fetuin-A as an inhibitor of ectopic mineralization is underscored by clinical studies showing that low fetuin-A serum levels are associated with calcification disease [19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Microvasculopathy, Luminal Calcification and Premature Aging in Fetuin-A Deficient Mice

Herrmann

Babler

Moshkova

et al. 2019

Preprint

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Objective -The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP) -rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore ectopic mineralization (calcification). The mutant mouse strain D2,Ahsg-/-combines fetuin-A deficiency with the mineralization-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue mineralization. Here we studied mechanisms leading to soft tissue mineralization, organ damage and premature aging in these mice.Approach and Results -We analyzed mice longitudinally by echocardiography, X-raycomputed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/-mice.Fetuin-A deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature aging. Importantly, early stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the ectopic mineralization was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis.Conclusions -Collectively, these results demonstrate that pathological mineralization can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of mineralized matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

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A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma

Cited by 30 publications

References 51 publications

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Microvasculopathy, Luminal Calcification and Premature Aging in Fetuin-A Deficient Mice

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