Clinical Pharmacokinetics and Pharmacodynamics of Fostamatinib and Its Active Moiety R406

Abstract

Fostamatinib is the first approved spleen tyrosine kinase inhibitor for chronic immune thrombocytopenia. This review summarizes the clinical development, pharmacokinetics, pharmacodynamics, drug-drug interactions, adverse events, and comprehensive analyses of fostamatinib. While integrating these findings, we discuss the fostering and improvement of fostamatinib for further clinical applications. Fostamatinib is designed as a prodrug and cleavage of its active moiety R406 in the intestine. As R406 is the major product in the blood, this review mainly discusses the pharmacokinetics and pharmacodynamics of R406. It is metabolized by cytochrome 3A4 and UGT1A9 in the liver and is dominantly excreted in feces after anaerobic modification by the gut microbiota. As fostamatinib and R406 strongly inhibit the breast cancer resistance protein, the interaction with those substrates, particularly statins, should be carefully monitored. In patients with immune thrombocytopenia, fostamatinib administration started at 100 mg twice daily, and most patients increased to 150 mg twice daily in the clinical trial. Although responders showed a higher R406 concentration than non-responders, the correlation between R406 exposure and achievement of the platelet count as a pharmacodynamic marker was uncertain in the pharmacokinetic/pharmacodynamic analysis. Additionally, R406 concentration was almost halved in patients with a heavy body weight; hence, the exposure-efficacy study for suitable dosing should be continued with post-marketing data. In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.

Fig. 1

Changes in pharmacodynamic markers over time during fostamatinib treatment. a American College of Rheumatology 20% improvement response rates over time in a phase III randomized clinical trial in patients with rheumatoid arthritis. Republished with permission of John Wiley & Sons [18]; permission conveyed through Copyright Clearance Center, Inc. b Median platelet levels over time in a phase III clinical trial for immune thrombocytopenia patients. Republished with permission of John Wiley & Sons [13]; permission conveyed through Copyright Clearance Center, Inc. bid twice daily, qd once daily

Fig. 2

Changes in basophil activation in the dose-dependent manner. Dose-dependent inhibition of basophil activation was observed after single dosing of R406 in healthy human volunteers. Heparinized blood was stimulated ex vivo with α immunoglobulin E, and changes in cell surface expression of CD63 were measured by flow cytometry. Republished with permission of American Society for Pharmacology and Experimental Therapeutics [35]; permission conveyed through Copyright Clearance Center, Inc.

Fig. 3

Graphical scheme of fostamatinib pharmacokinetics. Fostamatinib was designed as a prodrug cleaved to R406 by alkaline phosphatase in the intestine. R406 was mainly metabolized by cytochrome P450 (CYP) 3A4 and UGT1A9 in the liver. In human plasma, R406 and other three metabolites (M647, M633, and M537) were detected; however, these three accounted for less than 3%. In the human mass balance study, almost 80% of the radioactivity was recovered in feces, which consisted of two primary metabolites: one was R406 and the other was M413; the 3,5-benzene diol metabolite of R406. The other 20% of metabolites were eliminated into urine as an N-glucuronide R406 (M647)

Fig. 4

Plasma R406 concentration after a single oral administration of fostamatinib. Plasma R406 concentrations (ng/mL) in healthy human volunteers after an oral administration of a single dose of 80 mg, 250 mg, and 400 mg of fostamatinib in phase I clinical trial. Blood samples were collected at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 48, 56, 72, 96, and 120 h after dosing. Republished with permission of John Wiley & Sons [53]; permission conveyed through Copyright Clearance Center, Inc.