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Paul Martin - One of the best experts on this subject based on the ideXlab platform.
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Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of Fostamatinib: results from five phase I clinical studies
European Journal of Clinical Pharmacology, 2017Co-Authors: Talia Flanagan, Michael Gillen, Paul Martin, David Mathews, Eleanor Lisbon, Martin KruusmägiAbstract:Purpose Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. Methods A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two Fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. Results The in vivo performance of Fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of Fostamatinib was 54.6 %. Conclusions The absolute oral bioavailability of Fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.
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Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of Fostamatinib: results from five phase I clinical studies.
European journal of clinical pharmacology, 2016Co-Authors: Talia Flanagan, Michael Gillen, Paul Martin, David Mathews, Eleanor Lisbon, Martin KruusmägiAbstract:Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two Fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. The in vivo performance of Fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of Fostamatinib was 54.6 %. The absolute oral bioavailability of Fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.
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Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies
Clinical pharmacology in drug development, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Clive Brealey, David Lau, David J. Sweeny, Dominic Surry, Philip T. LeeseAbstract:Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of Fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of Fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2-106.8) and hydroxy pioglitazone (90.9; 78.6-105.1), an increase in pioglitazone AUC (117.8; 108.4-128.0), a decrease in hydroxy pioglitazone AUC(0-t) (89.7; 78.9-101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4-12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, Fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.
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solitary inhibition of the breast cancer resistance protein efflux transporter results in a clinically significant drug drug interaction with rosuvastatin by causing up to a 2 fold increase in statin exposure
Drug Metabolism and Disposition, 2016Co-Authors: Robert Elsby, Paul Martin, Dominic Surry, Pradeep Sharma, Katherine FennerAbstract:The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, Fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between Fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by Fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice.
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Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies
Drugs in R&D, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, Clive Brealey, David Mathews, J. Ritter, Dominic Surry, Victoria Holmes, P. Severin, Robert ElsbyAbstract:Background and objectives Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between Fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects.
Michael Gillen - One of the best experts on this subject based on the ideXlab platform.
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Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of Fostamatinib: results from five phase I clinical studies
European Journal of Clinical Pharmacology, 2017Co-Authors: Talia Flanagan, Michael Gillen, Paul Martin, David Mathews, Eleanor Lisbon, Martin KruusmägiAbstract:Purpose Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. Methods A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two Fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. Results The in vivo performance of Fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of Fostamatinib was 54.6 %. Conclusions The absolute oral bioavailability of Fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.
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Effects of ranitidine (antacid), food, and formulation on the pharmacokinetics of Fostamatinib: results from five phase I clinical studies.
European journal of clinical pharmacology, 2016Co-Authors: Talia Flanagan, Michael Gillen, Paul Martin, David Mathews, Eleanor Lisbon, Martin KruusmägiAbstract:Fostamatinib is an orally dosed phosphate prodrug that is cleaved by intestinal alkaline phosphatase to the active metabolite R406. Clinical studies were performed to assess the effect of food and ranitidine on exposure, to support in vitro-in vivo relationships (IVIVR) understanding and formulation transitions and to investigate absolute oral bioavailability. A series of in vitro dissolution and clinical pharmacokinetic studies were performed to support the design and introduction of a new formulation, understand the impact of changes in in vitro dissolution on in vivo performance for two Fostamatinib formulations, to characterize the effects of food and ranitidine on exposure, and determine the absolute oral bioavailability. The in vivo performance of Fostamatinib was generally insensitive to changes in in vitro dissolution performance, although marked slowing of the dissolution rate did impact exposures. Food and ranitidine had minor effects on R406 exposure that were not considered clinically relevant. The absolute oral bioavailability of Fostamatinib was 54.6 %. The absolute oral bioavailability of Fostamatinib was ~55 %. Food and ranitidine had minor effects on R406 exposure. An in vitro dissolution versus clinical performance relationship was determined that supported formulation transitions.
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Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies
Clinical pharmacology in drug development, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Clive Brealey, David Lau, David J. Sweeny, Dominic Surry, Philip T. LeeseAbstract:Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of Fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of Fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2-106.8) and hydroxy pioglitazone (90.9; 78.6-105.1), an increase in pioglitazone AUC (117.8; 108.4-128.0), a decrease in hydroxy pioglitazone AUC(0-t) (89.7; 78.9-101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4-12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, Fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.
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Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies
Drugs in R&D, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, Clive Brealey, David Mathews, J. Ritter, Dominic Surry, Victoria Holmes, P. Severin, Robert ElsbyAbstract:Background and objectives Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between Fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects.
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Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
Drugs in R&D, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Muhammad Baluom, Elliott B Grossbard, Clive Brealey, David Lau, David J. Sweeny, Tim MantAbstract:Background Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of Fostamatinib, R406, is primarily metabolized by CYP3A4.
James B Bussel - One of the best experts on this subject based on the ideXlab platform.
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Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia.
British journal of haematology, 2020Co-Authors: Ralph V. Boccia, Sandra Tong, Michael Boxer, Nichola Cooper, Quentin A. Hill, Michelle Sholzberg, Waleed Ghanima, Michael D. Tarantino, Leslie Todd, James B BusselAbstract:Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received Fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy (after ≥2 prior lines of therapy including a second-line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second-line and 54/113 (48%) third-or-later-line patients. Bleeding events were less frequent in second-line (28%) versus third-or-later-line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, Fostamatinib was more effective as second-line than third-or-later-line therapy for ITP.
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long term sustained response to Fostamatinib in two patients with chronic refractory immune thrombocytopenia itp
British Journal of Haematology, 2020Co-Authors: Eunju Lee, Marina Izak, James B BusselAbstract:Care of patients with chronic immune thrombocytopenia (ITP) who are refractory to available treatments can be quite challenging. Fostamatinib, an oral Syk inhibitor, is the newest FDA-approved agent for ITP. Phase 3 clinical trials demonstrated an overall response in 43% of patients treated with Fostamatinib and use for two years has been reported. Herein, we report two patients with long histories of ITP without lasting responses to numerous first-, second- and third-line therapies with prolonged responses to ongoing Fostamatinib. This shows that patients unresponsive to other agents may respond to Fostamatinib and can have sustained benefit.
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Long‐term sustained response to Fostamatinib in two patients with chronic refractory immune thrombocytopenia (ITP)
British journal of haematology, 2020Co-Authors: Eunju Lee, Marina Izak, James B BusselAbstract:Care of patients with chronic immune thrombocytopenia (ITP) who are refractory to available treatments can be quite challenging. Fostamatinib, an oral Syk inhibitor, is the newest FDA-approved agent for ITP. Phase 3 clinical trials demonstrated an overall response in 43% of patients treated with Fostamatinib and use for two years has been reported. Herein, we report two patients with long histories of ITP without lasting responses to numerous first-, second- and third-line therapies with prolonged responses to ongoing Fostamatinib. This shows that patients unresponsive to other agents may respond to Fostamatinib and can have sustained benefit.
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Potential Anti-Thrombotic Effect without Accompanying Hemorrhage with Fostamatinib Use in Patients with Immune Thrombocytopenia
Blood, 2019Co-Authors: Ivy Altomare, Robert P. Numerof, Esteban Masuda, Vadim Markovtsov, Leslie Todd, Dheepika Weerasinghe, Sandy Tong, James B BusselAbstract:Background Immune thrombocytopenia (ITP) results from autoimmune antibody-mediated destruction of platelets. Bruising and bleeding are hallmarks of ITP, but thromboembolic events (TEEs) are also observed in ITP patients, even thrombocytopenic ones. In population-based cohort studies, chronic ITP patients had two-fold higher risk of a venous TEE compared to the general population.1 The risk of venous or arterial TEE is further elevated in splenectomized ITP patients and those on thrombopoietin receptor agonists (TPO-RAs). Other risk factors include: age > 60 years, prolonged corticosteroid treatment, diabetes, hypertension, coronary disease, history of TEEs, presence of anti-phospholipid antibodies, chronic kidney disease, and male sex. Fostamatinib, an inhibitor of spleen tyrosine kinase (SYK), is approved for treatment of thrombocytopenia in adults with ITP. Extensive preclinical data suggest that inhibition of SYK signaling may also have an anti-thrombotic effect. In a model of acute stroke, mice with platelet-specific SYK deficiency were protected from aortic thrombosis and also had diminished size of brain infarction with only marginal effect on hemostasis.2 These results were reproduced by a SYK inhibitor in this model.2 We assessed rates of thrombosis among ITP patients treated with Fostamatinib compared to those reported with TPO-RAs. Methods We reviewed the incidence of TEEs during Fostamatinib clinical trials in ITP, including 2, randomized, double-blind, placebo-controlled, phase 3, multicenter clinical trials and an open-label extension study. The incidence of TEEs with TPO-RAs during published phase 3 clinical trials and post-phase 3 extension studies was also reviewed. Results The study population comprised 145 ITP patients who received Fostamatinib and included 37 (26%) patients >65 years, 51 (35%) splenectomized patients, and 58 (40%) male patients. The 3 Fostamatinib clinical trials represent 163 patient-years of Fostamatinib exposure. The only reported TEE was a transient ischemic attack (0.7%), which resolved spontaneously in a patient with pre-existing atherosclerosis. The rate of TEEs reported in ITP patients receiving TPO-RAs in multiple studies ranged from 0 to 9% (Table). Discussion The rate of TEEs observed in ITP patients receiving Fostamatinib was very low (< 1%) in comparison with the rates of TEEs reported in ITP patients receiving a TPO-RA (up to 9%). ITP patients have higher levels of prothrombin fragments 1 + 2, D-dimer, PAI-1 and soluble P-selectin, which contribute to a procoagulant profile. TPO-RA treatment may cause an increase in PAI-1, P-selectin, and increase microparticles and platelet apoptosis, all of which predispose to onset of TEEs.3,4 What explains the apparent paradox of Fostamatinib? SYK plays a key role in signaling of the ITAM receptors GPVI and CLEC-2 in platelets. Both GPVI and CLEC-2 play an important role in thrombosis but are dispensable for normal hemostasis. Consequently, SYK inhibition likely reduces the incidence of TEEs by abrogating the GPVI and CLEC-2 pathways in platelets. R406, the active metabolite of Fostamatinib, diminished GPVI and CLEC-2 mediated platelet aggregation with marginal effect on normal hemostasis in vivo.2,5 These mechanisms potentially explain why ITP patients treated with Fostamatinib are protected from developing TEEs despite often substantial platelet increases. SYK also plays a key role in Fcγ receptor dependent phagocytosis of auto-antibody coated platelets, the primary disease mechanism in ITP. Thus, SYK inhibition in ITP may simultaneously decrease platelet destruction (increasing platelet count) and decrease the incidence of TEEs. Suumary Current clinical trial experience with Fostamatinib in ITP patients demonstrates much lower rates of thrombosis than would be expected in ITP patients compared to other agents. Future work will prospectively evaluate this and confirm in vivo downregulation of platelet activation via inhibition of SYK signaling in platelets. 1. Rodeghiero F. Am J Hematol, 2016. 91: 39-45. 2. van Eeuwijk JM, et al. Arterioscler Thromb Vasc Biol, 2016. 36: 1247-53. 3. Garabet, L., et al. Platelets, 2019. 30: 206-12. 4. Justo Sanz, R., et al. Thromb Haemost, 2019. 119: 645-59. 5. Spalton, J.C., et al. J Thromb Haemost, 2009. 7: 1192-9. Disclosures Altomare: Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy; Incyte: Consultancy, Speakers Bureau. Markovtsov:Rigel: Employment, Equity Ownership. Todd:Rigel: Employment, Equity Ownership. Weerasinghe:Rigel: Employment. Numerof:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Masuda:Rigel: Consultancy, Employment, Equity Ownership. Bussel:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of Fostamatinib in other diseases is off-label.
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Long-term Fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program.
American journal of hematology, 2019Co-Authors: James B Bussel, Sandra Tong, Donald M. Arnold, Michael Boxer, Nichola Cooper, Hany Zayed, Jiri Mayer, Anne-marie DuliegeAbstract:Two randomized, double-blind, placebo-controlled studies demonstrated responses (≥50 000/μL) to Fostamatinib in adults with long-standing immune thrombocytopenia (ITP). The long-term safety and efficacy of Fostamatinib were evaluated in a follow-on, open-label extension (OLE) study. Patients received double-blind Fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/μL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/μL during weeks 1 to 12. A total of 146 patients received Fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/μL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty-seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/μL. Sixty-four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/μL and a median response duration of >28 months. Twenty-four of 71 (34%) patients who had failed TPO agents achieved overall responses to Fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.
Tim Mant - One of the best experts on this subject based on the ideXlab platform.
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Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
Drugs in R&D, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Muhammad Baluom, Elliott B Grossbard, Clive Brealey, David Lau, David J. Sweeny, Tim MantAbstract:Background Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of Fostamatinib, R406, is primarily metabolized by CYP3A4.
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Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies.
Clinical therapeutics, 2015Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Muhammad Baluom, Clive Brealey, David Lau, Robert Elsby, Tim MantAbstract:Abstract Purpose Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether Fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of Fostamatinib on the pharmacokinetic parameters of digoxin to understand drug–drug interaction (DDI) potential in the clinic. Methods Inhibition of P-gp–mediated digoxin transport by Fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC 50 ) and theoretical gastrointestinal concentration [I 2 ] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration–time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral Fostamatinib 100 mg BID on days 9 to 15. Findings Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC 50 = 3.2 μM). On the basis of a theoretical gastrointestinal concentration (I 2 )/IC 50 ratio of 216 ([I 2 ] = 691 μM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with Fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (C max,ss ) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of C max was earlier when digoxin was co-administered with Fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. Implications Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and Fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.
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pharmacokinetics of Fostamatinib a spleen tyrosine kinase syk inhibitor in healthy human subjects following single and multiple oral dosing in three phase i studies
British Journal of Clinical Pharmacology, 2013Co-Authors: Muhammad Baluom, Elliott B Grossbard, Tim MantAbstract:Aim Fostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of Fostamatinib and R406. Method Three clinical studies were conducted in healthy subjects: (A) A single ascending dose study for R406 with doses ranging from 80–600 mg, (B) a single- and multiple-dose study of Fostamatinib in aqueous suspension, with single doses ranging from 80–400 mg and multiple doses at 160 mg twice daily and (C) a study comparing suspension and tablet of Fostamatinib, with the latter tested in both fed and fasted states. Results These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12–21 h was observed. Similar R406 exposure could be achieved with Fostamatinib suspension and steady-state was achieved after 3–4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change. Conclusion Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of Fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once daily or twice daily oral administration of Fostamatinib.
David Millson - One of the best experts on this subject based on the ideXlab platform.
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Safety and efficacy of Fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-ASIA-1 and OSKIRA-ASIA-1X study.
Rheumatology (Oxford England), 2020Co-Authors: Yoshiya Tanaka, David Millson, Shigeru Iwata, Shingo NakayamadaAbstract:Objective The primary objectives of two phase II studies of Fostamatinib were to evaluate efficacy (OSKIRA-Asia-1: NCT01569074) and long-term safety/tolerability (OSKIRA-Asia-1X: NCT01640054) in patients from Asia with active RA despite MTX treatment. Methods OSKIRA-Asia-1 was a 12-week, multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive one of four Fostamatinib doses (groups A-D; n = 31, 33, 33, 33) or placebo (group E; n = 33). OSKIRA-Asia-1X was a long-term extension study (100 mg Fostamatinib qd) of patients who completed OSKIRA-Asia-1. RA signs and symptoms were measured by ACR response criteria and DAS based on a 28-joint count. Physical function status was assessed with the HAQ-Disability Index. Safety findings were monitored. Results In OSKIRA-Asia-1, Fostamatinib revealed numerical improvements in ACR 20% response (ACR20) at week 12 in group A (100 mg bid) and group B (100 mg bid, then 150 mg qd) vs placebo. Statistically significant improvements in ACR20 and ACR50 at week 8 and in ACR70 at week 12, and statistically significant achievement in low disease activity (defined as DAS based on a 28-joint count ≤3.2 based on C-reactive protein) occurred in groups A and B. Improvement in physical function was numerically higher in group A. The most common adverse events were hypertension, diarrhoea and neutropenia. In OSKIRA-Asia-1X, the most common adverse events were nasopharyngitis, hypertension, RA and neutropenia. Conclusion Fostamatinib achieved both statistically and clinically significant improvements in RA signs and symptoms. The safety and tolerability of Fostamatinib (plus MTX) were consistent with previous studies. Trial registration OSKIRA-Asia-1 trial registration: https://clinicaltrials.gov, NCT01569074; OSKIRA-Asia-1X trial registration: https://clinicaltrials.gov, NCT01640054.
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Effects of Fostamatinib on the Pharmacokinetics of the CYP2C8 Substrate Pioglitazone: Results From In Vitro and Phase 1 Clinical Studies
Clinical pharmacology in drug development, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Clive Brealey, David Lau, David J. Sweeny, Dominic Surry, Philip T. LeeseAbstract:Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of Fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of Fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2-106.8) and hydroxy pioglitazone (90.9; 78.6-105.1), an increase in pioglitazone AUC (117.8; 108.4-128.0), a decrease in hydroxy pioglitazone AUC(0-t) (89.7; 78.9-101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4-12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, Fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.
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Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies.
Drugs in R&D, 2016Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Muhammad Baluom, Elliott B Grossbard, Clive Brealey, David Lau, David J. Sweeny, Tim MantAbstract:Background Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of Fostamatinib, R406, is primarily metabolized by CYP3A4.
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Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies
Clinical therapeutics, 2015Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, T. Marbury, David MillsonAbstract:Abstract Purpose Phase III trials of Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of Fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. Methods Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of Fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of Fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a ≥1-week washout. In these patients, Fostamatinib was administered after dialysis or 2 hours before dialysis. Findings Geometric mean R406 C max and AUC values were less in the combined renally impaired group than in the group with normal renal function; T max was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when Fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 C max values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and T max values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and T max was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated. Implications In these patients, renal or hepatic impairment did not affect exposure to the active metabolite of Fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic).
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Effects of Fostamatinib on the Pharmacokinetics of Digoxin (a P-Glycoprotein Substrate): Results From in Vitro and Phase I Clinical Studies.
Clinical therapeutics, 2015Co-Authors: Paul Martin, Stuart Oliver, Michael Gillen, David Millson, Muhammad Baluom, Clive Brealey, David Lau, Robert Elsby, Tim MantAbstract:Abstract Purpose Fostamatinib, a spleen tyrosine kinase inhibitor and prodrug of the active metabolite R406, is being developed as an anti-inflammatory drug for several indications for which polypharmacy is likely. Digoxin, indicated for congestive cardiac failure, may be used for certain supraventricular dysrhythmias. The studies reported herein examined whether Fostamatinib and R406 are inhibitors of P-glycoprotein (P-gp) in vitro and evaluated the effect of Fostamatinib on the pharmacokinetic parameters of digoxin to understand drug–drug interaction (DDI) potential in the clinic. Methods Inhibition of P-gp–mediated digoxin transport by Fostamatinib and R406 was determined across Caco-2 cell monolayers. Apparent permeability of digoxin was determined and used to calculate efflux ratios and percentage inhibition. Half maximal inhibitory concentrations (IC 50 ) and theoretical gastrointestinal concentration [I 2 ] (dose in moles per 250 mL) were calculated to gauge clinical DDI potential. In a subsequent Phase I study, the plasma concentration–time profiles and resulting pharmacokinetic parameters were examined across 2 treatment periods: (1) oral digoxin loading dose of 0.25 mg BID on day 1 and 0.25 mg once daily on days 2 to 8, and (2) oral digoxin 0.25 mg once daily and oral Fostamatinib 100 mg BID on days 9 to 15. Findings Fostamatinib (but not R406) was determined to be a P-gp inhibitor in vitro (IC 50 = 3.2 μM). On the basis of a theoretical gastrointestinal concentration (I 2 )/IC 50 ratio of 216 ([I 2 ] = 691 μM), predictions indicated the potential for absorption-based DDI in vivo through inhibition of intestinal P-gp. In the clinical study, when digoxin was co-administered with Fostamatinib, digoxin levels were higher before dosing and throughout the dosing interval, and an increase in exposure to digoxin was observed. Co-administration led to a 1.70-fold increase in digoxin maximum plasma concentration at steady state (C max,ss ) versus digoxin administration alone (2.18 vs 1.32 ng/mL). Median digoxin time of C max was earlier when digoxin was co-administered with Fostamatinib (1.00 vs 1.48 hours). The digoxin AUC during the dosing interval at steady state was increased 1.37-fold with co-administration. No severe or serious adverse events or deaths were reported. Implications Fostamatinib was confirmed to be a P-gp inhibitor in vitro and in vivo, and a DDI with digoxin was apparent. Co-administration of digoxin and Fostamatinib was generally well tolerated. However, continued review of digoxin response and dose is advisable should these agents be prescribed concomitantly. ClinicalTrials.gov identifier: NCT01355354.