Fostamatinib

Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.

Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following fostamatinib doses of 100 mg twice daily for 28 days. About 31% of patients in the fostamatinib group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following fostamatinib discontinuation in 58% (11 of 19) of patients in the fostamatinib group who had blood pressures ≥140/90 mmHg.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, fostamatinib did not prolong the QT interval to a clinically relevant extent.

Fostamatinib is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for C_max and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).

Absorption

After oral administration of fostamatinib, the absolute bioavailability of R406 was 55%. The median t_max of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma.

Effect of Food

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 C_max by 15%.

Distribution

In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.

Elimination

The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours.

Metabolism

Fostamatinib is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, 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.

Excretion

Following an oral dose of fostamatinib, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O-desmethyl R406 and a metabolite produced by gut bacteria from the O-desmethyl metabolite of R406.

Specific Populations

Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of fostamatinib is not altered in patients 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).

Drug Interaction Studies

Clinical Pharmacology Studies

No significant interactions were seen with concomitant use of fostamatinib with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH).

Effect of Other Drugs on Fostamatinib

Strong CYP3A4 inhibitor: Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg fostamatinib (0.53 times the 150 mg dosage) increased R406 AUC by 102% and C_max by 37%.

Moderate CYP3A4 Inhibitor: Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg fostamatinib increased R406 AUC by 39% and C_max by 6%.

CYP3A4 inducer: Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg fostamatinib decreased R406 AUC by 75% and C_max by 59%.

Effect of Fostamatinib on Other Drugs

CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily fostamatinib increased simvastatin AUC by 64% and C_max by 113% and simvastatin acid AUC by 64% and C_max by 83%.

BCRP substrate: Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily fostamatinib increased rosuvastatin AUC by 95% and C_max by 88%.

P-gp substrate: Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily fostamatinib increased digoxin AUC by 37% and C_max by 70%.

In Vitro Studies

Fostamatinib is an inhibitor of the human P-gp efflux transporter in vitro.

CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity.

R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities.