Apixaban

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Charles Frost - One of the best experts on this subject based on the ideXlab platform.

  • Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma
    Thrombosis and Haemostasis, 2017
    Co-Authors: Robert J. Yetman, Jessie Wang, Yu Chen Barrett, Zhaoqing Wang, Robert Adamczyk, Eduardo Ramacciotti, Charles Frost
    Abstract:

    The objective was to characterise Apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth–≤1 month], infants [>1–≤6 months], toddlers [>6 months–≤2 years], young children [>2–≤6 years], children [>6–≤12 years], adolescents [>12–≤18 years]), and six adult (19–45 years) subjects. Plasma spiked with Apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223–0.295 IU/ml; 110 ng/ml: 1.212–1.474 IU/ml). Endogenous baseline factor X levels were 43%–68% lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both Apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for Apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4–53.2 s to 64.5–70.0 s); no prolongation was found with Apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition. Supplementary Material to this article is available at www.thrombosis-online.com.

  • The effect of Apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.
    Clinical pharmacology : advances and applications, 2017
    Co-Authors: Charles Frost, Jessie Wang, Yan Song, Alan Schuster, Lois Lee, Allyson Pollack, Frank Lacreta
    Abstract:

    Purpose Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of Apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on Apixaban PK in healthy subjects were investigated in two Phase 1 studies. Patients and methods The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2-10, followed by Apixaban 20 mg and digoxin 0.25 mg once daily on days 11-20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of Apixaban 10 mg, atenolol 100 mg, or Apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration-time curve (AUCtau), with and without Apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%-125% (digoxin) or 70%-143% (atenolol). A similar analysis was performed to assess the effect of atenolol on Apixaban. Results Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study. Conclusion Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between Apixaban and atenolol. Coadministration of digoxin or atenolol with Apixaban in healthy subjects was generally well tolerated.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa
    American Journal of Cardiovascular Drugs, 2016
    Co-Authors: Blisse Vakkalagadda, Wonkyung Byon, Rebecca A. Boyd, Charles Frost, Donglu Zhang, Jessie Wang, Clapton Dias, Andrew Shenker, Frank Lacreta
    Abstract:

    Objective Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous Apixaban were evaluated in an open-label, randomized, sequential crossover study. Methods Twenty healthy participants received single doses of Apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of Apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. Results Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced Apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous Apixaban and mean apparent clearance by 2.1-fold for oral Apixaban, indicating rifampin affected both pre-systemic and systemic Apixaban elimination pathways. Conclusion Co-administration of Apixaban with rifampin reduced Apixaban exposure via both decreased bioavailability and increased systemic clearance.

Jessie Wang - One of the best experts on this subject based on the ideXlab platform.

  • Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma
    Thrombosis and Haemostasis, 2017
    Co-Authors: Robert J. Yetman, Jessie Wang, Yu Chen Barrett, Zhaoqing Wang, Robert Adamczyk, Eduardo Ramacciotti, Charles Frost
    Abstract:

    The objective was to characterise Apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth–≤1 month], infants [>1–≤6 months], toddlers [>6 months–≤2 years], young children [>2–≤6 years], children [>6–≤12 years], adolescents [>12–≤18 years]), and six adult (19–45 years) subjects. Plasma spiked with Apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223–0.295 IU/ml; 110 ng/ml: 1.212–1.474 IU/ml). Endogenous baseline factor X levels were 43%–68% lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both Apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for Apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4–53.2 s to 64.5–70.0 s); no prolongation was found with Apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition. Supplementary Material to this article is available at www.thrombosis-online.com.

  • The effect of Apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.
    Clinical pharmacology : advances and applications, 2017
    Co-Authors: Charles Frost, Jessie Wang, Yan Song, Alan Schuster, Lois Lee, Allyson Pollack, Frank Lacreta
    Abstract:

    Purpose Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of Apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on Apixaban PK in healthy subjects were investigated in two Phase 1 studies. Patients and methods The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2-10, followed by Apixaban 20 mg and digoxin 0.25 mg once daily on days 11-20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of Apixaban 10 mg, atenolol 100 mg, or Apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration-time curve (AUCtau), with and without Apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%-125% (digoxin) or 70%-143% (atenolol). A similar analysis was performed to assess the effect of atenolol on Apixaban. Results Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study. Conclusion Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between Apixaban and atenolol. Coadministration of digoxin or atenolol with Apixaban in healthy subjects was generally well tolerated.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa
    American Journal of Cardiovascular Drugs, 2016
    Co-Authors: Blisse Vakkalagadda, Wonkyung Byon, Rebecca A. Boyd, Charles Frost, Donglu Zhang, Jessie Wang, Clapton Dias, Andrew Shenker, Frank Lacreta
    Abstract:

    Objective Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous Apixaban were evaluated in an open-label, randomized, sequential crossover study. Methods Twenty healthy participants received single doses of Apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of Apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. Results Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced Apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous Apixaban and mean apparent clearance by 2.1-fold for oral Apixaban, indicating rifampin affected both pre-systemic and systemic Apixaban elimination pathways. Conclusion Co-administration of Apixaban with rifampin reduced Apixaban exposure via both decreased bioavailability and increased systemic clearance.

Donglu Zhang - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa
    American Journal of Cardiovascular Drugs, 2016
    Co-Authors: Blisse Vakkalagadda, Wonkyung Byon, Rebecca A. Boyd, Charles Frost, Donglu Zhang, Jessie Wang, Clapton Dias, Andrew Shenker, Frank Lacreta
    Abstract:

    Objective Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous Apixaban were evaluated in an open-label, randomized, sequential crossover study. Methods Twenty healthy participants received single doses of Apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of Apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. Results Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced Apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous Apixaban and mean apparent clearance by 2.1-fold for oral Apixaban, indicating rifampin affected both pre-systemic and systemic Apixaban elimination pathways. Conclusion Co-administration of Apixaban with rifampin reduced Apixaban exposure via both decreased bioavailability and increased systemic clearance.

  • Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of Apixaban.
    British Journal of Clinical Pharmacology, 2014
    Co-Authors: Charles Frost, Wonkyung Byon, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Andrew Shenker, Yu Chen Barrett, Janice Pursley, Mohit D. Gandhi, Frank Lacreta
    Abstract:

    Aim To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and Apixaban (an oral, selective, direct factor-Xa inhibitor). Method In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of Apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of Apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid–induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. Results Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, Apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with Apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml−1, consistent with the Apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for Apixaban and naproxen, respectively). Conclusion Co-administration of naproxen with Apixaban results in higher Apixaban exposure and appears to occur through increased Apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of Apixaban and naproxen.

  • Investigating the enteroenteric recirculation of Apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.
    Drug Metabolism and Disposition, 2013
    Co-Authors: Donglu Zhang, Charles Frost, Kan He, A. David Rodrigues, Theunis C. Goosen, Lifei Wang, Xiaoli Wang, W. Griffith Humphreys
    Abstract:

    The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on Apixaban pharmacokinetics and disposition. The experimental approaches involve integrating Apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in Apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20–50% of an Apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of Apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of Apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that Apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of Apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of Apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of Apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on Apixaban disposition.

Rebecca A. Boyd - One of the best experts on this subject based on the ideXlab platform.

  • Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review
    Clinical Pharmacokinetics, 2019
    Co-Authors: Wonkyung Byon, Samira Garonzik, Rebecca A. Boyd, Charles E. Frost
    Abstract:

    Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of Apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3–4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total Apixaban clearance occurring via renal excretion. The pharmacokinetics of Apixaban are consistent across a broad range of patients, and Apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of Apixaban is closely correlated with Apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug–drug interaction profiles of Apixaban. Additionally, the population-pharmacokinetic analyses of Apixaban in both healthy subjects and in the target patient populations are discussed.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • pharmacokinetics pharmacodynamics and safety of Apixaban in subjects with end stage renal disease on hemodialysis
    The Journal of Clinical Pharmacology, 2016
    Co-Authors: Xiaoli Wang, Rebecca A. Boyd, Donglu Zhang, Jessie Wang, Yan Song, Janice Pursley, Giridhar Tirucherai, Thomas Marbury, Ming Chang, Charles Frost
    Abstract:

    An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of Apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of Apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of Apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, Apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in Apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in Apixaban concentration. A single 5-mg oral dose of Apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in Apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on Apixaban clearance.

  • Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa
    American Journal of Cardiovascular Drugs, 2016
    Co-Authors: Blisse Vakkalagadda, Wonkyung Byon, Rebecca A. Boyd, Charles Frost, Donglu Zhang, Jessie Wang, Clapton Dias, Andrew Shenker, Frank Lacreta
    Abstract:

    Objective Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous Apixaban were evaluated in an open-label, randomized, sequential crossover study. Methods Twenty healthy participants received single doses of Apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of Apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. Results Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced Apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous Apixaban and mean apparent clearance by 2.1-fold for oral Apixaban, indicating rifampin affected both pre-systemic and systemic Apixaban elimination pathways. Conclusion Co-administration of Apixaban with rifampin reduced Apixaban exposure via both decreased bioavailability and increased systemic clearance.

  • Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of Apixaban
    The Journal of Clinical Pharmacology, 2015
    Co-Authors: Ming Chang, Wonkyung Byon, Rebecca A. Boyd, Jessie Wang, Andrew Shenker, Frank Lacreta, Janice Pursley, Charles Frost
    Abstract:

    This open-label study evaluated Apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between Apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed. Secondary objectives included assessment of safety and tolerability as well as international normalized ratio (INR) and anti-factor Xa activity as pharmacodynamic endpoints. The regression analysis showed that decreasing renal function resulted in modestly increased Apixaban exposure (AUC∞ increased by 44% in severe impairment with a 24-hour CLcr of 15 mL/min, compared with subjects with normal renal function), but it did not affect Cmax or the direct relationship between Apixaban plasma concentration and anti-factor Xa activity or INR. The assessment of renal function measured by iohexol clearance, Cockcroft-Gault, and MDRD was consistent with that determined by 24-hour CLcr . Apixaban was well tolerated in this study. These results suggest that dose adjustment of Apixaban is not required on the basis of renal function alone.

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  • real world comparison of bleeding risks among non valvular atrial fibrillation patients prescribed Apixaban dabigatran or rivaroxaban
    PLOS ONE, 2018
    Co-Authors: Ping G Tepper, Jack Mardekian, Hemant Phatak, Cristina Masseria, Shital Kamble, Younos Abdulsattar, William Petkun, Gregory Y H Lip
    Abstract:

    Limited real-world data are available regarding the comparative safety of non-vitamin K antagonist oral anticoagulants (NOACs). The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed Apixaban, dabigatran, or rivaroxaban. NVAF patients aged ≥18 years with a 1-year baseline period were included if they were new initiators of NOACs or switched from warfarin to a NOAC. Cox proportional hazards modelling was used to estimate the adjusted hazard ratios of any bleeding, clinically relevant non-major (CRNM) bleeding, and major inpatient bleeding within 6 months of treatment initiation for rivaroxaban and dabigatran compared to Apixaban. Among 60,227 eligible patients, 8,785 were prescribed Apixaban, 20,963 dabigatran, and 30,529 rivaroxaban. Compared to dabigatran or rivaroxaban patients, Apixaban patients were more likely to have greater proportions of baseline comorbidities and higher CHA2DS2-VASc and HAS-BLED scores. After adjusting for baseline clinical and demographic characteristics, patients prescribed rivaroxaban were more likely to experience any bleeding (HR: 1.35, 95% confidence interval [CI]: 1.26–1.45), CRNM bleeding (HR: 1.38, 95% CI: 1.27–1.49), and major inpatient bleeding (HR: 1.43, 95% CI: 1.17–1.74), compared to patients prescribed Apixaban. Dabigatran patients had similar bleeding risks as Apixaban patients. In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding, compared to Apixaban patients. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding risks between patients treated with dabigatran and Apixaban.

  • real world use of Apixaban for stroke prevention in atrial fibrillation a systematic review and meta analysis
    Stroke, 2018
    Co-Authors: Marco Proietti, Imma Romanazzi, Giulio Francesco Romiti, Alessio Farcomeni, Gregory Y H Lip
    Abstract:

    Background and Purpose— The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on Apixaban for stroke prevention in atrial fibrillation. Methods— We performed a systematic review and meta-analysis of all observational real-world studies comparing Apixaban with other available oral anticoagulant drugs. Results— From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, Apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64–0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for Apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for Apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with Apixaban when compared with all oral anticoagulant agents ( P Conclusions— Use of Apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with Apixaban compared with warfarin, dabigatran, and rivaroxaban.

  • major bleeding risk among non valvular atrial fibrillation patients initiated on Apixaban dabigatran rivaroxaban or warfarin a real world observational study in the united states
    International Journal of Clinical Practice, 2016
    Co-Authors: Jack Mardekian, Gregory Y H Lip, Xianying Pan, Cristina Masseria, Shital Kamble, Hugh Kawabata, Amanda Bruno, Hemant Phatak
    Abstract:

    SummaryBackground Limited data are available about the real-world safety of non-vitamin K antagonist oral anticoagulants (NOACs). Objectives To compare the major bleeding risk among newly anticoagulated non-valvular atrial fibrillation (NVAF) patients initiating Apixaban, warfarin, dabigatran or rivaroxaban in the United States. Methods and results A retrospective cohort study was conducted to compare the major bleeding risk among newly anticoagulated NVAF patients initiating warfarin, Apixaban, dabigatran or rivaroxaban. The study used the Truven MarketScan® Commercial & Medicare supplemental US database from 1 January 2013 through 31 December 2013. Major bleeding was defined as bleeding requiring hospitalisation. Cox model estimated hazard ratios (HRs) of major bleeding were adjusted for age, gender, baseline comorbidities and co-medications. Among 29 338 newly anticoagulated NVAF patients, 2402 (8.19%) were on Apixaban; 4173 (14.22%) on dabigatran; 10 050 (34.26%) on rivaroxaban; and 12 713 (43.33%) on warfarin. After adjusting for baseline characteristics, initiation on warfarin [adjusted HR (aHR): 1.93, 95% confidence interval (CI): 1.12–3.33, P=.018] or rivaroxaban (aHR: 2.19, 95% CI: 1.26–3.79, P=.005) had significantly greater risk of major bleeding vs Apixaban. Dabigatran initiation (aHR: 1.71, 95% CI: 0.94–3.10, P=.079) had a non-significant major bleeding risk vs Apixaban. When compared with warfarin, Apixaban (aHR: 0.52, 95% CI: 0.30–0.89, P=.018) had significantly lower major bleeding risk. Patients initiating rivaroxaban (aHR: 1.13, 95% CI: 0.91–1.41, P=.262) or dabigatran (aHR: 0.88, 95% CI: 0.64–1.21, P=.446) had a non-significant major bleeding risk vs warfarin. Conclusion Among newly anticoagulated NVAF patients in the real-world setting, initiation with rivaroxaban or warfarin was associated with a significantly greater risk of major bleeding compared with initiation on Apixaban. When compared with warfarin, initiation with Apixaban was associated with significantly lower risk of major bleeding. Additional observational studies are required to confirm these findings.

  • bleeding during treatment with aspirin versus Apixaban in patients with atrial fibrillation unsuitable for warfarin the Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitam
    Stroke, 2012
    Co-Authors: Greg C Flaker, Gregory Y H Lip, John W Eikelboom, Olga Shestakovska, Stuart J Connolly, Scott Kaatz, Andrzej Budaj, Steen Husted, Salim Yusuf, Robert G Hart
    Abstract:

    Background and Purpose— Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with Apixaban and aspirin. Methods— The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either Apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding. Results— The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with Apixaban (hazard ratio with Apixaban, 1.18; 95% CI, 0.92–1.51; P =0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to Apixaban and aspirin were use of nonstudy aspirin >50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS 2 scores but Apixaban compared with aspirin was associated with a similar relative risk of bleeding ( P interaction 0.21) and a reduced relative risk of stroke ( P interaction 0.37) irrespective of CHADS 2 category. Conclusions— Anatomic sites and predictors of bleeding are similar for Apixaban and aspirin in these patients. Higher CHADS 2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of Apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information— www.clinicaltrials.gov. Unique identifier: NCT 00496769.