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Fostamatinib (formerly also known as R788; trade name: Tavalisse), a prodrug of the active metabolite R406, is an orally bioactive, potent and selective Syk inhibitor with potential anti-inflammatory activity. It inhibits Syk with an IC50 of 41 nM in a cell-free assay. On April 17th 2018, Fostamatinib was approved by the US FDA for the treatment of thrombocytopenia in adult patients with persistent or chronic immune thrombocytopenia (ITP).
Physicochemical Properties
| Molecular Formula | C23H26FN6O9P | |
| Molecular Weight | 580.46 | |
| Exact Mass | 580.148 | |
| CAS # | 901119-35-5 | |
| Related CAS # | Fostamatinib Disodium;1025687-58-4;Fostamatinib disodium hexahydrate;914295-16-2 | |
| PubChem CID | 11671467 | |
| Appearance | White to off-white solid powder | |
| Density | 1.5±0.1 g/cm3 | |
| Boiling Point | 814.2±75.0 °C at 760 mmHg | |
| Flash Point | 446.2±37.1 °C | |
| Vapour Pressure | 0.0±3.1 mmHg at 25°C | |
| Index of Refraction | 1.629 | |
| LogP | 2.12 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 15 | |
| Rotatable Bond Count | 10 | |
| Heavy Atom Count | 40 | |
| Complexity | 904 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | GKDRMWXFWHEQQT-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C23H26FN6O9P/c1-23(2)21(31)30(11-38-40(32,33)34)20-14(39-23)6-7-17(28-20)27-19-13(24)10-25-22(29-19)26-12-8-15(35-3)18(37-5)16(9-12)36-4/h6-10H,11H2,1-5H3,(H2,32,33,34)(H2,25,26,27,28,29) | |
| Chemical Name | [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
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| ln Vivo | In Louvain rats, fostamatinib (R788) is highly bioavailable and rapidly absorbed. AUC0–16 hours were 10618 ng*h/mL and 30650 ng*h/mL, respectively; Cmax=2600 ng/mL and 6500 ng/mL (1 hour observation); t1/2=4.2 hours were recorded in R406 following a single oral dosage of R788 10 mg/kg or 20 mg/kg. The absence of prodrug in plasma suggests that R788 has fully transformed into R406 [1]. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Fostmatinib is the methylene phosphate prodrug of R406, the active metabolite. It is extensively hydrolyzed by intestinal alkaline phosphatase. Only negligible amounts of fostamatinib enter systemic circulation. R406 has an absolute bioavailability of 55% and reaches peak plasma concentrations in approximately 1.5 h. Administration with a high calorie, high fat meal increases exposure by 23% and the maximum plasma concentration by 15%. This may lengthen time to peak plasma concentration to approximately 3 h. Exposure to R406 is known to be dose proportional up to 200 mg twice daily. R406 accumulates 2-3 fold with twice daily dosing at 100-160 mg. About 80% of R406 is excreted in the feces, primarily as the O-glucuronide conjugate and the O-desmethyl metabolite produced by gut bacteria. The remaining 20% is excreted in the urine as the N-glucuronide conjugate. R406 has an apparent oral volume of distribution of approximately 400 L. R406 has an apparent oral clearance of approximately 300 mL/min. Metabolism / Metabolites Fostamatinib is metabolized in the gut by alkaline phosphatase to the active metabolite R406. R406 is further oxidized by CYP3A4 and glucuronidated by UGT1A9. Plasma metabolites found include an O-glucuronide conjugate, an N-glucuronide conjugate, an O-desmethyl metabolite, and a sulfate conjugate. A 3,5 benzene diol metabolite forms in the feces via processing of the O-desmethyl metabolite by gut bacteria. Biological Half-Life R406 has a half-life of elimination of approximately 15 h. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity In prelicensure controlled trials, serum aminotransferase elevations above 3 times ULN arose in 9% of fostamatinib treated subjects but in none of the placebo recipients. ALT values above 5 times ULN occurred in 5% of treated subjects. These elevations were typically transient but led to early discontinuations in a proportion of patients, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to fostamatinib. Since approval and more widescale availability of fostamatinib, there have been no published reports of hepatotoxicity associated with its use, although it has had limited general use. Likelihood score: E* (suspected but unproven cause of idiosyncratic clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of fostamatinib during breastfeeding. Because the active metabolite of fostamatinib (R406) is 98.3% bound to plasma proteins, the amount in milk is likely to be low. However, the active metabolites has a half-life of 15 hours, and might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during fostamatinib therapy and for at least 1 month after the final dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding R406 is 98.3% bound to plasma proteins. |
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| References |
[1]. Fostamatinib Disodium. Drugs Future. 2011;36(4):273. [2]. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008. [3]. A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther. 2006 May;317(2):571-8. |
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| Additional Infomation |
Pharmacodynamics The active metabolite of fostamatinib, R406, inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP. This results in increased platelet counts in this population. R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively. It can also inhibit signalling via Fcε receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation. Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib. As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor α, leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor. Fostamatinib can produce hypertension through off-target effects |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (3.58 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (3.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.. Solubility in Formulation 4: 4% DMSO+30% PEG 300+ddH2O:5 mg/mL Solubility in Formulation 5: 10 mg/mL (17.23 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; Need ultrasonic and warming and heat to 40°C. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7228 mL | 8.6139 mL | 17.2277 mL | |
| 5 mM | 0.3446 mL | 1.7228 mL | 3.4455 mL | |
| 10 mM | 0.1723 mL | 0.8614 mL | 1.7228 mL |