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The effect of rifampin on the pharmacokinetics of edoxaban in healthy adults.

Mendell J, Chen S, He L, Desai M, Parasramupria DA - Clin Drug Investig (2015)

Bottom Line: Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %.Edoxaban was well tolerated in this healthy adult population.PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

View Article: PubMed Central - PubMed

Affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ, 08837, USA, jmendell@dsi.com.

ABSTRACT

Background and objective: The oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study.

Methods: This was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 × 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed.

Results: In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population.

Conclusions: Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

No MeSH data available.


Related in: MedlinePlus

Mean plasma concentration–time curves of edoxaban (a) and the edoxaban metabolites M4 (b) and M6 (c) with and without rifampin. Edoxaban = a single oral dose of edoxaban 60 mg. Edoxaban with rifampin = 7 days of rifampin 600 mg (2 × 300 mg capsules once daily) followed by a single oral dose of edoxaban 60 mg administered concomitantly on day 7. Error bars represent standard deviations. The insets show semi-log scale plots
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Fig1: Mean plasma concentration–time curves of edoxaban (a) and the edoxaban metabolites M4 (b) and M6 (c) with and without rifampin. Edoxaban = a single oral dose of edoxaban 60 mg. Edoxaban with rifampin = 7 days of rifampin 600 mg (2 × 300 mg capsules once daily) followed by a single oral dose of edoxaban 60 mg administered concomitantly on day 7. Error bars represent standard deviations. The insets show semi-log scale plots

Mentions: The mean plasma edoxaban concentrations were similar for edoxaban alone and for edoxaban with rifampin up to the time when mean Cmax was reached (Fig. 1a). Plasma edoxaban concentrations declined faster when edoxaban was coadministered with rifampin than when it was administered alone.Fig. 1


The effect of rifampin on the pharmacokinetics of edoxaban in healthy adults.

Mendell J, Chen S, He L, Desai M, Parasramupria DA - Clin Drug Investig (2015)

Mean plasma concentration–time curves of edoxaban (a) and the edoxaban metabolites M4 (b) and M6 (c) with and without rifampin. Edoxaban = a single oral dose of edoxaban 60 mg. Edoxaban with rifampin = 7 days of rifampin 600 mg (2 × 300 mg capsules once daily) followed by a single oral dose of edoxaban 60 mg administered concomitantly on day 7. Error bars represent standard deviations. The insets show semi-log scale plots
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4488474&req=5

Fig1: Mean plasma concentration–time curves of edoxaban (a) and the edoxaban metabolites M4 (b) and M6 (c) with and without rifampin. Edoxaban = a single oral dose of edoxaban 60 mg. Edoxaban with rifampin = 7 days of rifampin 600 mg (2 × 300 mg capsules once daily) followed by a single oral dose of edoxaban 60 mg administered concomitantly on day 7. Error bars represent standard deviations. The insets show semi-log scale plots
Mentions: The mean plasma edoxaban concentrations were similar for edoxaban alone and for edoxaban with rifampin up to the time when mean Cmax was reached (Fig. 1a). Plasma edoxaban concentrations declined faster when edoxaban was coadministered with rifampin than when it was administered alone.Fig. 1

Bottom Line: Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %.Edoxaban was well tolerated in this healthy adult population.PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

View Article: PubMed Central - PubMed

Affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ, 08837, USA, jmendell@dsi.com.

ABSTRACT

Background and objective: The oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study.

Methods: This was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 × 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed.

Results: In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population.

Conclusions: Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

No MeSH data available.


Related in: MedlinePlus