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.

Fostamatinib for the treatment of Japanese patients with primary immune thrombocytopenia: A phase 3, placebo‐controlled, double‐blind, parallel‐group study

“…At the same time, as indicated by the distribution patterns of plasma R406 concentrations of responders and non‐responders (Figure S4), no clear exposure‐response relationship was observed in our study. In addition, a population pharmacokinetic/pharmacodynamic analysis using data from two phase 3 studies in ITP patients showed a higher R406 concentration in responders than in non‐responders at week 12, but not between weeks 14–24 or at week 24, ruling out any relationship between R406 exposure and efficacy 27–29 …”

“…In addition, a population pharmacokinetic/pharmacodynamic analysis using data from two phase 3 studies in ITP patients showed a higher R406 concentration in responders than in non-responders at week 12, but not between weeks 14-24 or at week 24, ruling out any relationship between R406 exposure and efficacy. [27][28][29] ITP patients treated with TPO-RAs experience an increased risk of thrombosis and platelet overshoot. [9][10][11] In our study, treatment with fostamatinib did not lead to platelet overshoot (>400 000/μl) or thromboembolic AEs.…”

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

“…Fostamatinib has been tested in various immune-mediated diseases such as RA, chronic immune thrombocytopenia, autoimmune hemolytic anemia, and IgA nephropathy [ 105 ]. It is the first SYKi approved for the treatment of chronic immune thrombocytopenia by blocking signal transduction through Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells [ 106 ].…”

Three classic synthetic paths of fostamatinib and its applications

“…Fostamatinib is initially appeared as a new means for RA treatment because it was found to have important affection in amplifying synovial inflammation, but after experiments found that Fostamatinib had a high probability of AE during treatment, and the therapeutic effect was lower than that of adalimumab, so it did not pass the regulatory application [3]. In 2009, fostamatinib was discovered to inhibit platelets of macrophages by inhibiting Syk [3]. Two parallel controlled trials FIT1 (NCT02076399) and FIT2 (NCT02076412) showed that fostamatinib had a significant effect on platelets, and it was acknowledged by the FDA after 9 years.…”

“…R788 is rapidly hydrolyzed by intestinal alkaline phosphatase to R406, and R406 is absorbed by the human body. And the related products can be mainly observed in plasma [3]. According to the results of the radiotracer, R406 is distributed to the outer position of the blood vessel, and the steady-state volume of distribution is 256±92.…”