Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa

Vakkalagadda, Blisse; Frost, Charles; Byon, Wonkyung; Boyd, Rebecca A.; Wang, Jessie; Zhang, Donglu; Zhang, Yu; Dias, Clapton; Shenker, Andrew; LaCreta, Frank

doi:10.1007/s40256-015-0157-9

Cited by 98 publications

(113 citation statements)

References 35 publications

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“…Renal clearance is estimated to represent approximately 27% of the total clearance of apixaban in healthy subjects 14 based on the results of 2 studies following intravenous administration. 15,16 The observed increase in apixaban exposure in subjects with ESRD is consistent with this estimate and suggests no impact of ESRD on apixaban absorption or other pathways of elimination. Furthermore, this result is consistent with the 44% increase in apixaban exposure in subjects with severe renal impairment (CL cr , 15 mL/min) observed in a previous study.…”

Section: Discussionsupporting

confidence: 81%

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

Wang

Tirucherai

Marbury

et al. 2015

The Journal of Clinical Pharma

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259

243

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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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Section: Discussionsupporting

confidence: 81%

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

Wang

Tirucherai

Marbury

et al. 2015

The Journal of Clinical Pharma

Self Cite

259

243

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show abstract

“…Apixaban has a total clearance of 3.3 L/hour, a steady‐state volume of distribution of ~21 liters, and a half‐life of ~12 hours following oral administration 8, 9. Multiple pathways are involved in the plasma elimination of apixaban, including metabolism primarily by cytochrome P450 3A4 (CYP3A4), and biliary, renal, and direct intestinal excretion 8, 10, 11, 12.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Cirincione

Kowalski²,

Nielsen³

et al. 2018

CPT Pharmacom & Syst Pharma

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This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.

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“…Rivaroxaban, apixaban and edoxaban are directly administered in an active form. Their bioavailability is incomplete (DE: 7% [1], Apixaban: 50% [2], Edoxaban: 60% [3], Rivaroxaban: 80% [4]) mainly due to a limited solubility. Bioavailability is not influenced by food intake except for rivaroxaban [4].…”

Section: Absorptionmentioning

confidence: 99%

“…As DOACs are substrates of P-gp and CYP3A, there are exposed to potential drug-drug interactions with strong P-gp/CYP3A inhibitors or inducers [2,3,[17][18][19][20][21]. Table 1 summarizes the known effects of such drugs on DAOC exposure.…”

Section: Efflux Transports and Drug-drug Interactionsmentioning

confidence: 99%

Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism

Bertoletti

Ollier

Duvillard

et al. 2017

Pharmacological Research

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Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa

Abstract: Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.

Cited by 98 publications

References 35 publications

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism

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