Chemical formula: C₂₃H₂₆FN₆O₉P Molecular mass: 580.46 g/mol PubChem compound: 11671467
Fostamatinib mediates its activity effectively through its major metabolite, R406, which is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). R406 inhibits signal transduction of B-cell receptors and Fc-activating receptors, which play a key role in antibody-mediated cellular responses. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.
Following oral administration, the prodrug fostamatinib is rapidly converted to its active metabolite R406, presumably via enzymes in the gut.
After oral administration of fostamatinib, the mean absolute bioavailability of R406 was 55% with high variability (range 30–85%). The median Tmax of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma.
After a single 150 mg oral dose of fostamatinib, mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2 670) ng/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dose). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dose).
Fostamatinib is highly bound to plasma proteins (98.3% in human plasma) and distributes reversibly into blood cells. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.
Fostamatinib is metabolised in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolised, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites.
In humans, the mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours. Approximately 20% of the administered radioactivity was recovered in the urine, primarily in the form of an N-glucuronide of R406. Renal elimination of parent medicinal product was low. The remaining radioactivity (~80%) was recovered in the faeces, mainly represented by 2 major metabolites of R406.
R406 pharmacokinetics is linear and exposure is approximately dose-proportional up to 200 mg twice daily (1.3 times the 150 mg dose). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100-160 mg (0.67 to 1.06 times the 150 mg dose).
Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and Cmax by 15%, indicating fostamatinib can be administered with or without food.
Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity.
The pharmacokinetics of fostamatinib is not altered in subjects with renal impairment (creatinine clearance [CLcr] = 30 to <50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C).
In two fostamatinib 4-week rat studies (with the calcium and sodium salts), chondrodystrophy of the femoral head was observed in some animals in the highest dose groups (that were still juvenile/young during the treatment interval) and was not fully reversible by the end of the recovery period.
In a 1-month study in juvenile rabbits, fostamatinib produced growth plate dysplasia in the proximal femur and femoro-tibial joint and reduced bone marrow cellularity in the femur and sternum at 30 and 60 mg/kg/day. Increased degenerate/necrotic ovarian follicles occurred in females at all fostamatinib dose levels (including 10 mg/kg/day). The changes noted in the growth plates and ovaries are consistent with an anti-angiogenic effect.
Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage at 45 mg/kg/day. Fostamatinib and its major active metabolite (R406) were not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay.
Studies in animals have shown no adverse effect on male fertility. Given there is no evidence for mutagenic or clastogenic potential, there is no concern for male-mediated birth defects. In a fertility study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in male rats were unaffected by doses as high as 40 mg/kg/day. This dose yields an AUC of R406 approximately 3.8 times that of the MRHD. All mating and fertility parameters in female rats were unaffected by doses as high as 11 mg/kg/day. This dose would yield an AUC of R406 similar to that of the MRHD. A slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day. This dose would yield an AUC of R406 2.6 times that of the MRHD.
In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-foetal mortality (post-implantation loss), alterations to growth (lower foetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD) respectively.
A slight decrease in pregnancy rates and an increase in post-implantation loss in female rats was observed. Nonclinical studies have established that the administration of fostamatinib during pregnancy can increase the risk of embryonic loss, retard growth, and promote specific malformations of the kidney (including agenesis) and associated urogenital (e.g. ureter) tissues, as well as variations/malformations in major vessel and skeletal development. These effects are consistent with known targets of fostamatinib, including Syk (target), VEGFR-2 (off target) and Ret-kinase (off target). Based on nonclinical studies, any latent issues with female fertility is not expected after fostamatinib is withdrawn.
In pregnant rats and rabbits, R406 was found to cross the placenta. In general, the maternal plasma R406 concentrations were greater than the foetal plasma R406 concentrations.
In rodents, R406 was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma.
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