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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 √ó 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

Pharmacodynamic effects of edoxaban with and without rifampin on (a) the mean prothrombin time and (b) the mean activated partial thromboplastin time. 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. The error bars represent standard deviations
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Fig2: Pharmacodynamic effects of edoxaban with and without rifampin on (a) the mean prothrombin time and (b) the mean activated partial thromboplastin time. 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. The error bars represent standard deviations

Mentions: The mean baseline PT and aPTT values were similar for both treatments. The PT and aPTT values at 2 and 4 h were minimally different with and without rifampin (Fig. 2). Coadministration of rifampin and edoxaban resulted in minimal changes (<10 %) from the baseline PT and aPTT values, compared with administration of edoxaban alone. However, these data should be interpreted with caution, as only early anticoagulatory effects were assessed.Fig. 2


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)

Pharmacodynamic effects of edoxaban with and without rifampin on (a) the mean prothrombin time and (b) the mean activated partial thromboplastin time. 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. The error bars represent standard deviations
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Pharmacodynamic effects of edoxaban with and without rifampin on (a) the mean prothrombin time and (b) the mean activated partial thromboplastin time. 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. The error bars represent standard deviations
Mentions: The mean baseline PT and aPTT values were similar for both treatments. The PT and aPTT values at 2 and 4 h were minimally different with and without rifampin (Fig. 2). Coadministration of rifampin and edoxaban resulted in minimal changes (<10 %) from the baseline PT and aPTT values, compared with administration of edoxaban alone. However, these data should be interpreted with caution, as only early anticoagulatory effects were assessed.Fig. 2

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 √ó 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