Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies

Abstract

Background and objectivesFostamatinib 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.MethodsThe OC study was a crossover study over two 28-day treatment periods (Microgynon® 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8–20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout.ResultsFostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration–time curve at steady state (AUCss) 28 % [confidence interval (CI 90 %) 21–36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34 % (CI 26–43)], but not levonorgestrel (AUCss 5 %; Cmax,ss −3 %), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈20 %). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18 % (CI 13–23) and 13 % (CI 7–19)]. Fostamatinib increased rosuvastatin AUC by 96 % (CI 78–115) and Cmax by 88 % (CI 69–110), and increased simvastatin acid AUC by 74 % (CI 50–102) and Cmax by 83 % (CI 57–113).ConclusionFostamatinib exhibits drug–drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-015-0120-x) contains supplementary material, which is available to authorized users.

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

“…Although rosuvastatin was not used as the in vitro probe to assess OATP1B1 and BCRP inhibition potential, estradiol 17b-glucuronide is a surrogate for OATP1B1-mediated rosuvastatin transport (Izumi et al, 2015), and for BCRP, even if a fostamatinib IC 50 value using rosuvastatin was 100-fold higher than that obtained versus estrone 3-sulfate, it would not change DDI potential or predictions. The data reproduced from the clinical interaction study by Martin et al (2016) demonstrated that sole inhibition of BCRP by fostamatinib resulted in a clinically significant approximately 2-fold increase in rosuvastatin exposure (AUC and C max ). Examination of rosuvastatin concentration-time profiles (Fig.…”

“…The mean plasma concentration-time profiles (0-96 hours) of a single oral dose of rosuvastatin (20 mg) when administered alone or concomitantly with 100 mg of fostamatinib at steady state (dosed twice daily for 5 days) are shown in Fig. 3 (reprinted from Martin et al, 2016). Fostamatinib increased the geometric least-squares mean AUC and C max of rosuvastatin by 96% (90% confidence interval, 78-115) and 88% (90% confidence interval, 69-110), respectively, indicating a clinical pharmacokinetic interaction (Martin et al, 2016).…”

“…3 (reprinted from Martin et al, 2016). Fostamatinib increased the geometric least-squares mean AUC and C max of rosuvastatin by 96% (90% confidence interval, 78-115) and 88% (90% confidence interval, 69-110), respectively, indicating a clinical pharmacokinetic interaction (Martin et al, 2016).…”

“…Recently, a clinical interaction study (NCT01725230, D4300C00039) between fostamatinib and rosuvastatin performed in healthy volunteers (62% Caucasian, 38% black ethnicity; 95% male and 5% female between the ages of 18 and 55 years, with body weight .50 kg and body mass index between 18 and 30 kg/m 2 ) was fully described and reported elsewhere (Martin et al, 2016). In brief, the study was an open-label, fixed-sequence study that assigned eligible subjects to receive 20 mg of rosuvastatin over two treatment periods: alone for period 1 and in combination with fostamatinib at steady state (100 mg twice daily for 5 days) for period 2.…”

“…b Fostamatinib (R788). (LC-MS/MS) methodologies and used to determine pharmacokinetic parameters (AUC and C max ) by noncompartmental modeling, as reported in Martin et al (2016).…”