Eur J Clin Pharmacol (2014) 70:1339–1351 DOI 10.1007/s00228-014-1736-4
PHARMACOKINETICS AND DISPOSITION
Edoxaban population pharmacokinetics and exposure–response analysis in patients with non-valvular atrial fibrillation Ophelia Q. P. Yin & Kimura Tetsuya & Raymond Miller
Received: 11 April 2014 / Accepted: 18 August 2014 / Published online: 29 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure–response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF). Methods Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients. Results Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V2), resulting in a predicted increase of 33–77 % in area under the curve (AUC) and 65–104 % in Cmax. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C24, −24 to 38 %), due to decreased V2 and shortened elimination half-life. With IV dosing of edoxaban, coadministration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V2, resulting in an increase of 32 % in AUC and 66 % in C24. Creatinine clearance was a
Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1736-4) contains supplementary material, which is available to authorized users. O. Q. P. Yin (*) : R. Miller Modeling and Simulation Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, USA e-mail: [email protected] K. Tetsuya Daiichi Sankyo Co., Ltd., Tokyo, Japan
significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Modelpredicted steady state Cmin was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure–response analysis suggested that edoxaban Cmin and country/region are significantly associated with the incidence of bleeds. Conclusions The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon coadministration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials. Keywords Edoxaban . Population pharmacokinetics . Exposure–response
Introduction Edoxaban is a novel direct inhibitor of activated factor Xa (FXa), a key enzyme located at the confluence of the intrinsic and extrinsic coagulation pathways. It binds to both free FXa and FXa within prothrombinase complex, thereby producing a dose-dependent decrease in thrombin generation [1]. The clinical antithrombotic activity of edoxaban has been demonstrated with oral administration of the drug [2, 3]. Based on the results from a phase II dose-finding study in patients with atrial fibrillation (AF), edoxaban once daily (QD) at 30 and 60 mg was selected for evaluation in two ongoing large-scale phase III trials, for the prevention of stroke and systemic
1340
embolism in patients with non-valvular atrial fibrillation (ENGAGE AF-TIMI 48 [4, 5]) and for the treatment and prevention of venous thromboembolism in patients with acute deep vein thrombosis and/or pulmonary embolism (HokusaiVTE [6]). In the ENGAGE AF-TIMI 48 study, edoxaban at 30 mg QD and 60 mg QD was demonstrated to be non-inferior to warfarin with respect to the prevention of stroke or systemic embolism and associated with significantly lower rates of bleeding and death from cardiovascular causes [5]. In the Hokusai-VTE study, after initial treatment with heparin, edoxaban QD was shown to be non-inferior to vitamin K antagonist therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism [6]. The pharmacokinetics of edoxaban has been extensively studied in healthy subjects. Following oral administration, the maximum plasma concentration of edoxaban occurs within 1 to 2 h. The oral bioavailability of edoxaban is estimated to be 61.8 %, based on an absolute bioavailability study in healthy subjects [7]. The plasma protein binding of edoxaban is relatively low, ranging from 40 to 59 % [8]. Edoxaban is eliminated via both renal excretion and liver metabolism pathways, with approximately 50 % of systemically absorbed drug being excreted in the urine. The most abundant metabolites are formed through hydrolysis with minor contribution from the cytochrome P450 3A [9, 10]. While hepatic impairment does not seem to affect edoxaban pharmacokinetics (PK) [11, 12], systemic exposure of edoxaban was found to increase significantly in subjects with varying degrees of renal impairment, in comparison to those with normal renal function. Edoxaban is also a substrate of P-glycoprotein (P-gp). Several drug–drug interaction studies have shown that the systemic exposure of edoxaban increases upon concomitant administration of various P-gp inhibitors, such as verapamil, quinidine, and amiodarone [7, 13, 14]. Since both intrinsic and extrinsic factors may contribute to the variability in edoxaban PK and the change in the systemic exposure may impact the efficacy and safety profiles of edoxaban, it is important to identify and quantify these contributing factors. In this manuscript, we evaluated the population PK of edoxaban, including the estimation of its bioavailability and quantification of the effects of P-gp inhibitors as well as the impact of renal impairment on edoxaban PK. The PK profiles and corresponding dose adjustment scheme of edoxaban have been assessed previously in patients with moderate renal impairment [15], but not those with severe renal impairment. Thus, in parallel to the assessment of renal effect, a specific objective was to explore a dose reduction scheme in patients with severe renal impairment. In addition, the relationship between edoxaban exposure and safety measures (bleeding events) was reassessed in AF patients who participated in a phase II dose-finding study.
Eur J Clin Pharmacol (2014) 70:1339–1351
Methods Study design A total of 11 studies, including eight phase I, one phase II, and two phase III studies, were included in the analysis (Table 1). All studies were approved by the institutional review board or independent ethics committee and were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Study 1 [7] evaluated the absolute bioavailability of edoxaban as well as the effect of the P-gp inhibitor, quinidine, on the PK of an intravenous dose of edoxaban. Edoxaban was given as a single 30 mg intravenous (IV) dose or 60 mg oral dose. Studies 2–6 [14] evaluated the effects of various P-gp inhibitors, ketoconazole, verapamil, erythromycin, quinidine, and amiodarone, on the PK of an oral dose of edoxaban, respectively. Edoxaban was given as a single oral 60 mg dose in each of these studies. Studies 7–10 assessed the impact of renal function on the edoxaban PK in different groups of subjects. Specifically, study 7 [16] included four parallel groups of subjects with normal renal function or with mild [creatinine clearance (CLcr) ≥50 to ≤80 mL/min], moderate (CLcr ≥30 to
PHARMACOKINETICS AND DISPOSITION
Edoxaban population pharmacokinetics and exposure–response analysis in patients with non-valvular atrial fibrillation Ophelia Q. P. Yin & Kimura Tetsuya & Raymond Miller
Received: 11 April 2014 / Accepted: 18 August 2014 / Published online: 29 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure–response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF). Methods Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients. Results Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution (V2), resulting in a predicted increase of 33–77 % in area under the curve (AUC) and 65–104 % in Cmax. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C24, −24 to 38 %), due to decreased V2 and shortened elimination half-life. With IV dosing of edoxaban, coadministration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V2, resulting in an increase of 32 % in AUC and 66 % in C24. Creatinine clearance was a
Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1736-4) contains supplementary material, which is available to authorized users. O. Q. P. Yin (*) : R. Miller Modeling and Simulation Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837, USA e-mail: [email protected] K. Tetsuya Daiichi Sankyo Co., Ltd., Tokyo, Japan
significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Modelpredicted steady state Cmin was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure–response analysis suggested that edoxaban Cmin and country/region are significantly associated with the incidence of bleeds. Conclusions The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon coadministration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials. Keywords Edoxaban . Population pharmacokinetics . Exposure–response
Introduction Edoxaban is a novel direct inhibitor of activated factor Xa (FXa), a key enzyme located at the confluence of the intrinsic and extrinsic coagulation pathways. It binds to both free FXa and FXa within prothrombinase complex, thereby producing a dose-dependent decrease in thrombin generation [1]. The clinical antithrombotic activity of edoxaban has been demonstrated with oral administration of the drug [2, 3]. Based on the results from a phase II dose-finding study in patients with atrial fibrillation (AF), edoxaban once daily (QD) at 30 and 60 mg was selected for evaluation in two ongoing large-scale phase III trials, for the prevention of stroke and systemic
1340
embolism in patients with non-valvular atrial fibrillation (ENGAGE AF-TIMI 48 [4, 5]) and for the treatment and prevention of venous thromboembolism in patients with acute deep vein thrombosis and/or pulmonary embolism (HokusaiVTE [6]). In the ENGAGE AF-TIMI 48 study, edoxaban at 30 mg QD and 60 mg QD was demonstrated to be non-inferior to warfarin with respect to the prevention of stroke or systemic embolism and associated with significantly lower rates of bleeding and death from cardiovascular causes [5]. In the Hokusai-VTE study, after initial treatment with heparin, edoxaban QD was shown to be non-inferior to vitamin K antagonist therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism [6]. The pharmacokinetics of edoxaban has been extensively studied in healthy subjects. Following oral administration, the maximum plasma concentration of edoxaban occurs within 1 to 2 h. The oral bioavailability of edoxaban is estimated to be 61.8 %, based on an absolute bioavailability study in healthy subjects [7]. The plasma protein binding of edoxaban is relatively low, ranging from 40 to 59 % [8]. Edoxaban is eliminated via both renal excretion and liver metabolism pathways, with approximately 50 % of systemically absorbed drug being excreted in the urine. The most abundant metabolites are formed through hydrolysis with minor contribution from the cytochrome P450 3A [9, 10]. While hepatic impairment does not seem to affect edoxaban pharmacokinetics (PK) [11, 12], systemic exposure of edoxaban was found to increase significantly in subjects with varying degrees of renal impairment, in comparison to those with normal renal function. Edoxaban is also a substrate of P-glycoprotein (P-gp). Several drug–drug interaction studies have shown that the systemic exposure of edoxaban increases upon concomitant administration of various P-gp inhibitors, such as verapamil, quinidine, and amiodarone [7, 13, 14]. Since both intrinsic and extrinsic factors may contribute to the variability in edoxaban PK and the change in the systemic exposure may impact the efficacy and safety profiles of edoxaban, it is important to identify and quantify these contributing factors. In this manuscript, we evaluated the population PK of edoxaban, including the estimation of its bioavailability and quantification of the effects of P-gp inhibitors as well as the impact of renal impairment on edoxaban PK. The PK profiles and corresponding dose adjustment scheme of edoxaban have been assessed previously in patients with moderate renal impairment [15], but not those with severe renal impairment. Thus, in parallel to the assessment of renal effect, a specific objective was to explore a dose reduction scheme in patients with severe renal impairment. In addition, the relationship between edoxaban exposure and safety measures (bleeding events) was reassessed in AF patients who participated in a phase II dose-finding study.
Eur J Clin Pharmacol (2014) 70:1339–1351
Methods Study design A total of 11 studies, including eight phase I, one phase II, and two phase III studies, were included in the analysis (Table 1). All studies were approved by the institutional review board or independent ethics committee and were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Study 1 [7] evaluated the absolute bioavailability of edoxaban as well as the effect of the P-gp inhibitor, quinidine, on the PK of an intravenous dose of edoxaban. Edoxaban was given as a single 30 mg intravenous (IV) dose or 60 mg oral dose. Studies 2–6 [14] evaluated the effects of various P-gp inhibitors, ketoconazole, verapamil, erythromycin, quinidine, and amiodarone, on the PK of an oral dose of edoxaban, respectively. Edoxaban was given as a single oral 60 mg dose in each of these studies. Studies 7–10 assessed the impact of renal function on the edoxaban PK in different groups of subjects. Specifically, study 7 [16] included four parallel groups of subjects with normal renal function or with mild [creatinine clearance (CLcr) ≥50 to ≤80 mL/min], moderate (CLcr ≥30 to
