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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.

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  • 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.

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  • 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.

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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.

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  • 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.

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  • 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.

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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.

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  • 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.

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  • 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, Donglu Zhang, Charles Frost, 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.

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