Appendix:

Old and new oral anticoagulant drugs: pharmacokinetics.

1. Vitamin K: pathophysiology

Vitamin K is key for the biosynthesis of coagulation factors II, VII, IX and X. A poor Vitamin K

recycling results in a strong anticoagulant activity [1]. Vitamin K is a molecular cofactor in the

conversion of the protein-bound amino acid glutamate into γ-carboxyglutamic acid (Gla). This step

is catalyzed by the γ-glutamate carboxylase (GGCX), an enzyme present in the endoplasmic

reticulum in a variety of mammalian cells. Vitamin K is a coenzyme for GGCX. The oxidation of

Vitamin K hydroquinone provides the energy for the carboxylation of the terminal Gla residue of

Vitamin K–dependent clotting-factors. Low Vitamin K is needed to enable this carboxylation in the

liver.

2. Vitamin K antagonists (VKAs)

Vitamin K antagonists (VKAs) include: warfarin, phenprocoumon and acenocoumarol.

Pharmacokinetics parameters of VKAs, as reviewed by Ufer et al. [2] are summarized in Online

Table S1. Except for S-acenocoumarol, which undergoes extensive first-pass metabolism, VKAs

are rapidly and extensively absorbed from the stomach and small intestine after oral administration

with essentially complete oral bioavailability [3]. As the protein bound of VKAs is high in human

plasma (≈98-99%), and as only the free fraction is pharmacologically active, variations in plasma

levels of albumin affect VKAs activity [4].

The apparent volume of distribution of warfarin is comparable to that of phenprocoumon and it is

≈50% of that of acenocoumarol [2]. These three drugs are almost completely metabolized in

specific pathways depending on the drug and R- and S-enantiomeric form [5]. The R-isomer is

metabolized by cytochrome P450 1A2 and 3A4 isozymes. The S-isomer is >90% metabolized by

the cytochrome P450 2C9 isozyme (CYP2C9) [6].

1

Both acenocoumarol and phenprocoumon share a common mechanism of action with warfarin as

they inhibit non-competitively the Vitamin K epoxide reductase complex subunit 1 (VKORC1) and,

consequently, the internal recycling of oxidized Vitamin K to reduced Vitamin K. Vitamin K also

serves as a co-factor for other Gla-containing entities, such as anticoagulant proteins C, S and Z

[7]. Thus, VKAs regulate the pro-coagulant and the natural anti-coagulant system.

2.1. Warfarin

Warfarin is a racemic mixture, S-warfarin being ≈2 to 4 times more potent in terms of anticoagulant

activity than the R-enantiomer. The degree of anticoagulation reflects the extent of warfarin

exposure as well as the pre-existing hepatic levels of Vitamin K. Pharmacokinetics of warfarin is

summarized in Online Table S1. Warfarin has an essentially complete oral bioavailability [3].

Xenobiotics (including drugs and herbal medicines) that induce or inhibit cytochrome P450 1A2

and 3A4 isozymes (which metabolizes the R-isomer) [6] and cytochrome P450 2C9 isozyme

(which metabolizes the S-isomer)[6] impair warfarin metabolism and decrease or increase the PT-

INR, respectively.

Given the high potency of the S-isomer, genetic polymorphisms of CYP2C9, as well as its

inhibitors or inducers, modulate the expression and activity of such isozyme, and regulate the

antithrombotic potential of warfarin by affecting plasma warfarin concentrations at any given dosing

rate. In humans, hydroxylation and reduction processes account for the metabolic clearance of

warfarin (≈80% in urine and 20% in feces). The R-enantiomer is hydroxylated by CYP 1A2, 2C8,

2C19 and 3A4 isozymes.

2.2. Phenprocoumon

Phenprocoumon is structurally derived from 4-hydroxycoumarin. Pharmacokinetics parameters of

phenprocoumon, as reviewed by Ufer et al. [2], are summarized in Online Table S1. Reduced

clearance by the cytochrome CYP P450 enzymes involved in phenprocoumon hydroxylation and

enterohepatic recycling of conjugated phenprocoumon are probably the main cause of the longer

t1/2 of phenprocoumon [2]. CYP2C9 and CYP3A4 are the major enzymes responsible for the

2

metabolism of phenprocoumon. In vitro, approximately 60% and 40% of metabolites are formed by

CYP2C9 and CYP3A4, respectively [5]. However, at variance with the dramatic impact on warfarin

metabolism, CYP2C9 and VKORC1 polymorphisms impact moderately the responsiveness of

phenprocoumon [5].

2.3. Acenocoumarol

Similar to phenprocoumon, acenocoumarol is structurally derived from 4-hydroxycoumarin.

Acenocoumarol has almost double apparent volumes of distribution than warfarin and

phenprocoumon (Online Table S1) [2]. CYP2C9 hydroxylates all of the S-form of acenocoumarol

and approximately 60% of the R-enantiomer. The 6- and 7-hydroxylated metabolites and trace

amounts of the parent compound are then excreted in their non-conjugated form via the kidneys

[5]. At variance with the dramatic impact on warfarin metabolism, CYP2C9 and VKORC1

polymorphisms impact moderately the responsiveness of acenocoumarol [5].

3. DOACs

3.1. Dabigatran

Dabigatran etexilate is a synthetic, reversible, low-molecular weight, competitive non-active direct

thrombin inhibitor (DTI) pro-drug [8] that is administered orally and hydrolyzed by non-specific

ubiquitous (gut, liver, plasma) esterases to its active form Dabigatran [9; 10]. Dabigatran binds to

and potently inhibits the catalytic site of thrombin [11] and, at variance with heparin [12], inactivates

both unbound and fibrin-bound thrombin from continuously triggering thrombus formation/extension

(i.e. activating platelets, amplifying the coagulation process, converting fibrinogen to fibrin, cross-

linking fibrin monomers and inhibiting fibrinolysis) [13].

The absolute bioavailability of oral dabigatran etexilate is ≈6% (Online Table S1), implying that the

recommended doses of dabigatran ensure adequate plasma concentrations with no unexpected

accumulation after multiple dosing [14]. After oral administration to healthy volunteers of dabigatran

etexilate, containing capsules filled with micropellets of the drug surrounding a tartaric acid core,

3

Cmax is reached within 0.5–2 hrs [15]. After multiple-dose administration, steady-state plasma

concentrations are achieved within 3 days [16]. Dabigatran etexilate absorption is dependent on,

and enhanced by, an acidic microenvironment, which reduces drug variability [17]. Accordingly,

dabigatran etexilate absorption is independent of gastrointestinal tract acidity, and no dose

adjustment is needed when co-administered with a proton pump inhibitor (PPI) [17]. Dabigatran

clearance exhibits a bi-exponential decline. Regardless of the dose, the mean t½ β is ≈8–10 hrs

after a single oral dose, and ranges 14-17 hrs after multiple doses [18]. In older healthy volunteers,

the t½ is ≈12–14 hrs, and is increased to 28 hrs in those with a creatinine-clearance (CrCl) of ≤30

mL/min [19]. For patients with moderate renal impairment (CrCl of 30 to 50 ml/min), the

recommended dose is one 150-mg capsule twice daily (BID). However, for patients with a high risk

of bleeding, including patients 75 to 80 years of age, one 110-mg capsule BID should be

considered [20]. No dose adjustment is needed in patients with mild renal impairment (CrCl of 50

to 80 ml/min), while dabigatran should be used with caution in those with a CrCl of ≤50 ml/min.

Dabigatran etexilate is not metabolized by the CYP enzymes or other oxidoreductases. About 20%

is conjugated with glucuronic acid and excreted via the biliary system [21]. After a single oral dose

of dabigatran etexilate to patients with mild hepatic impairment, the area under the curve (AUC) is

comparable with that of healthy control subjects, and the conversion of the pro-drug is only slightly

reduced [22]. Up to 80% of circulating unchanged dabigatran and small amounts of dabigatran

glucuronides are excreted unchanged by the kidneys.

3.2. Rivaroxaban

Rivaroxaban is a potent, highly selective, reversible oral direct inhibitor of FXa that prevents

thrombin generation regardless whether free, prothrombinase bound, or associated with a clot [23].

Rivaroxaban does not inhibit the function of major coagulation-related serine proteases such as

thrombin, trypsin, plasmin, Factor VIIa, IXa, or XIa, urokinase or activated protein C [24]. Nor a

direct effect has been shown on the function of platelets [25]. The pharmacokinetics of rivaroxaban

has been evaluated in healthy young males (aged 19–45 years) and in older subjects (60–76

years) at single oral doses (up to 80 mg) [26] and multiple doses (up to 30 mg BID) [27].

4

Rivaroxaban is rapidly absorbed after oral administration and reaches peak plasma concentrations

(Cmax) in 2–4 hrs, the longer time to Cmax (tmax) being observed when rivaroxaban is co-

administered with food. Co-administration with food is associated with a 30–40% increase in the

AUC and a reduced inter-patient variability, hence increasing the predictability of plasma

concentrations of Rivaroxaban [28]. Accordingly, the drug has been administered mostly with food

(and often in combination with antiplatelet drugs) in randomized clinical trials. When steady-state

conditions are achieved, dose-proportional increases in the AUC, with no significant drug

accumulation are observed [27]. The pharmacokinetic profile of rivaroxaban in healthy subjects is

not affected by age or sex, nor its profile is affected by mild hepatic impairment (Child-Pugh class

A) [29]. In contrast, the AUC is two-fold higher than in controls, and inhibition of FXa activity is

increased (i.e. the PT is prolonged) in subjects with moderate hepatic impairment (Child-Pugh

class B) [30]. The Cmax is unaffected when rivaroxaban is given to subjects weighing ≥120 kg,

whereas it is increased (by ≈ ¼) when the drug is given to those weighing ≤50 kg [31]. Both in

patients undergoing total hip replacement and in those treated for venous thromboembolism, Cmax

values are higher and trough levels lower with once-daily than with twice-daily dosing [32]. Plasma

protein binding is 92–95%, serum albumin being the predominant binding component. Rivaroxaban

has a terminal elimination half-life (t ½ β) of 5–9 hrs in healthy young subjects [27], and, due to

normal age-related renal function decline, 11–13 hrs in elderly subjects [33]. Compared with

healthy controls with values ≥80 ml/min, the AUC for single-dose rivaroxaban is ≈1.5-fold higher in

individuals with severe (ClCr 15–29 mL/min) renal impairment, similar increases in the AUC being

found in those with mild (ClCr 50–80 mL/min) or moderate (ClCr 30–49 mL/min) impairment [34].

Rivaroxaban should not be used in those with a CrCl of ≤15 ml/min. About two-third of ingested

rivaroxaban is excreted via the kidneys, the rest being excreted in the feces as unchanged drug. Of

that excreted in the urine, 30–40% is unchanged drug excreted via a combination of glomerular

filtration and tubular secretion, and 60–70% is metabolized [35]. In the liver, rivaroxaban is

metabolized via CYP enzymes-independent and CYP-dependent (CYP3A4 and CYP2C8)

mechanisms [36].

5

3.3. Apixaban

Apixaban is a highly selective reversible, pyrazole derivative direct FXa inhibitor with no effect on

activated protein C, Factors IXa and VIIa, and platelet aggregation in response to a variety of

stimuli.[37] Apixaban prevents thrombin generation in vitro [38] and, similar to rivaroxaban, inhibits

FXa regardless of whether it is prothrombinase or clot-bound, or it is free.[39] Improved

antithrombotic activity and moderate, significant increase in bleeding time is achieved by adding

aspirin or clopidogrel to apixaban.[40; 41] In healthy adult volunteers, apixaban is rapidly absorbed,

reaching Cmax approximately 3 to 4 hrs after oral administration [42]. For 10 mg doses, the

bioavailability of apixaban is ≈50% (Online Table S1), and steady-state concentrations are reached

within 3 days, with a mean t½ of 12.7 ± 8.6 hrs; thus, it is given twice daily for all indications [43].

Apixaban has a low volume of distribution, ≈ 21 L, and is ≈87% protein bound [39]. While food has

little effect [44], body weight, sex and age exert major effects on apixaban Cmax or AUC. In healthy

males and females, after a single oral dose of 10 mg apixaban, the Cmax and AUC are 30 and 20%

higher, respectively, in subjects weighing ≤50 kg than in those weighing 65–85 kg, and 30 and

20% lower, respectively, than in subjects weighing ≥120 kg [45]. A single oral dose of 20 mg

apixaban led to a 32% and 7% higher Cmax and AUC, respectively, in older (65 years) than in

younger (18–40 years) healthy individuals (males and females) and a 18% and 15% higher Cmax

and AUC, respectively, in women than in men [46]. Hence, the recommended dose of apixaban for

stroke prevention in AF is 5 mg BID, a 2.5-mg BID dose being recommended in patients with ≥2 of

the following criteria: age 80 years and older, body weight ≤60 kg, or a serum creatinine level of

≥1.5 mg/dl (133 µmol/l). After oral administration, the drug is excreted by multiple routes, with

approximately 50% recovered unchanged in the feces and ≈ ¼ excreted in the urine [42]. There

are limited clinical data in patients with a CrCl of 15 to 29 ml/min. Consequently, apixaban should

be used with caution in such patients and the drug is not recommended in patients with CrCl ≤15

ml/min. Apixaban is metabolized in the liver via O-demethylation and hydroxylation mainly by

CYP3A4/5, with minor contributions from CYP1A2 and 2J2 enzymes. ≈ ¼ of the dose administered

is excreted unchanged in the urine [47].

6

3.4. Edoxaban

Edoxaban is a once-daily highly oral direct FXa inhibitor that selectively inhibits factor Xa in a

concentration-dependent manner [48]. In healthy subjects, edoxaban is rapidly absorbed and

reaches Cmax in 1–3 hrs [49]. In healthy volunteers receiving edoxaban 60 mg, AUC and Cmax are

not affected by enoxaparin (1 mg/kg), either administered concomitantly or 12 hrs apart [50]. In

healthy subjects, edoxaban has a half-life of approximately 10–14 hrs and its absolute oral

bioavailability is 62% [51]. Plasma protein binding is lower than that of apixaban or rivaroxaban

(≈55% vs 87% and 90%, respectively). Accordingly, hemodialysis does not affect protein binding,

exposure or clearance of edoxaban [52]. Nor do food intake, ethnicity or gender influence

edoxaban absorption, elimination, Cmax, and half-life [53]. The majority of an edoxaban dose is

excreted within 24 hrs, and ≥70% of the absorbed drug is excreted unchanged in the urine [54].

The rest of edoxaban is metabolized to various derivatives, the most abundant of which (M4) is

formed through hydrolysis [54]. Edoxaban is eliminated in feces and urine and, compared with

dabigatran (85%) or rivaroxaban (66%), a lower proportion of its administered dose is excreted via

the kidneys (35%) [54].

7

Online Table S1.Old and new oral anticoagulants: Comparative pharmacokinetics and pharmacodynamics.

VKAs [2] DOACs [55]

Variable Warfarin Phenprocoumon Acenocoumarol Dabigatran* Apixaban Rivaroxaban Edoxaban

TargetVitamin K-dependent

proteinsVitamin K-dependent

proteinsVitamin K-dependent

proteinsThrombin (IIa) Factor Xa Factor Xa Factor Xa

Dose (mg/day)

Variable,

(1.5-12) [56; 57] (PT-INR dependent)

Variable,

(0.75-9) [58]

Variable,

(1-9) [59]

Fixed

(110-150)

Fixed

(2.5-5) [60]

Fixed

(15-20)

Fixed

(30-60)

Frequency of administration

Once daily Once daily Once daily Twice daily Twice daily Once daily Once daily

Anticoagulation monitoring

PT-INR PT-INR PT-INRHemoclot (Diluted

Thrombin time)

Rotachrom

Anti-Xa (Plasma calibrators needed)

Rotachrom

Anti-Xa (Plasma calibrators needed)

Rotachrom

Anti-Xa (Plasma calibrators needed)

Plasma concentrations† 1.5-8 µmol/L [57] 1.5-15 µmol/L [61] 0.03-0.3 µmol/L [59] 110 ng/ml [62] 470 ng/ml [62] 141-173 ng/ml [62]

303 ng/ml [63]

Vd (L/kg) 0.08-0.12 [64] 0.11-0.14 [58] 0.22-0.52 [3] 70 [65] 21 [66] 50 [66] 107 [67]

Tmax, hours 72-96 Variable [68] Variable (1-3) [68] 0.5-2.0 [65] 3-4 [65] 2-4 [65] 1-3 [49]

Transport proteins none None [69] None [69] P-gP [65] P-gP, BCRP [65] P-gP, BCRP [65] P-gP [60]

T1/2, hoursEn. S: 24-33 [70]

En. R: 35-58 [70]

En. S: 110-130 [71]

En. R: 110-125 [71]

En. S: 1.8 [3] ††

En. R: 6.6 [3] ††12-14 [65] 12 (8-15) [65]

5-9 (young)

11-13 (elderly) [65]10-14 [51]

Plasma clearance (L/hrs)

En. S: 0.10-1.00 [57]

En. R: 0.07-0.35 [57]

En. S: 0.045-0.055 [71]

En. R: 110-125 [71]

En. S: 28.5 [3] ††

En. R: 1.9 [3] ††105–170 [62] 3 [62] 10 [62] 21.8 [67]

8

Plasma protein binding >99% [57] >99% [4] >98% [4] 35% [65] 87% [65] 92-95% [65] 55% [52]

Bioavailability >95% [68] >95% [68] >95% [68] 6.5% [65] 50% [65]66% without food,

~100% with food [65]62% [51]

Elimination Kinetics First-order [64] First-order [58] Biphasic [72]First-order [21]

Biphasic [73]

First-order [74] Biphasic [74]

Liver metabolism

En S: 2C9 [75]

En R: 1A2, 3A4, 2C8, 2C19 [75]

En S: 2C9, 2C8, 3A4 [75]

En R: 3A4, 2C9 [75]

En S: 2C9 [75]

En R: 1A2, 3A4, 2C9, 2C19 [75]

No [65] CYP3A4 (25%) [65] CYP3A4 (~66%) [65] CYP3A4 (<4%) [60]

Renal Elimination§ <1% [68] <1% [68] <1% [68] 85% [65]

27%

if renal function is normal [65]

66% (half as inactive metabolite)

if renal function is normal [65]

35-50% [44]

if renal function is normal

Antidote° Vitamin K Vitamin K Vitamin K Idarucizumab** [76] Andexanet Alfa*** [76]Andexanet Alfa***

[76]Andexanet Alfa***

[76]

Absorption with H2B/PPI

No effect No data available No data available

Reduction of plasma level from

12 to 30%

Adjustment not needed

No effect No effect No effect

Asian ethnicity No effect No data available No data available Plasma level +25% No effect No effect No effect [53]

Gastro intestinal tolerability

Good Good GoodDyspepsia

(5-10%)Good Good Good

Effect of Body weight

Obese patients may require a 30% to 50% increase with the initial dosing of VKA [77]

Obese patients may require a 30% to 50%

increase with the initial dosing of VKA

[77]

Obese patients may require a 30% to 50%

increase with the initial dosing of VKA

[77]

Cmin:

20% decrease in subjects >100 kg [65]

Exposure:

30% increase in subjects <50 kg

30% decrease in subjects >120 kg [65]

Exposure:

25% increase in subjects <50 kg

25%decrease in subjects >120 kg [65]

Exposure:

increase in subjects <60 kg

9

Effect of ageDependent on liver

function

Older patients (>70 y) requires a dose 30% lower than younger

patients [78]

Acenocumarol requirements

decrease with aging [79]

Cmin: 31% increase in subjects ≥75 yrs [65]

AUC: 32% increase in subjects ≥65 yrs [65]

AUC: 50% increase in subjects ≥65 yrs

[65]None

Effect of foodVariable (Intake with food to be avoided)

No data available No data available

Prolongs Tmax to 2 h

(Intake with food discouraged) [65]

No effect

(Intake with food discouraged) [65]

Mean AUC increases to ≈40%

(Intake with food mandatory) [80]

No effect

(Intake with food: no official

recommendation) [53]

Effect of genderFemale may need lower dosage [66]

No data available

Acenocumarol requirement is higher in women aged 40-50 years compared with

men [79]

None [65]

Exposure:

18% higher in females [65]

None [65] None [53]

In pregnancy Contraindicated Contraindicated Contraindicated Contraindicated Contraindicated Contraindicated Contraindicated

Interactions with drugsCYP3A4/1A2/2C9

inhibitors and inducers, food [66]

CYP3A4/CYP2C9 inhibitors and inducers, food

CYP3A4/CYP2C9 inhibitors and inducers, food

Strong P-gp inhibitors and inducers [65]

Strong P-gp and CYP3A4 inhibitors and inducers [65]

Strong P-gp and CYP3A4 inhibitors and inducers [65]

Strong P-gp inhibitors [44]

Abbreviations: CYP=cytochrome P450; P-gP=P glycoprotein; BCRP=breast cancer resistance protein. Vd=Volume of distribution.

* prodrug.

** (BI 655075; Boehringer Ingelheim), humanized murine monoclonal antibody fragment (Fab).

*** (r-Antidote, PRT064445; Portola Pharmaceuticals), recombinant truncated enzymatically inactive factor Xa which reverses the anticoagulant action

of factor Xa inhibitors.

§ In those receiving DOACs, frequent laboratory monitoring is needed if creatinine clearance is 20-50 mL/min). DOACs are contraindicated if creatinine

clearance is < 20 mg/dl.

† For VKAs: Total plasma concentration of bound and unbound racemic drug after maintenance doses; for DOACs: maximum concentration.

†† As related to subjects expressing the CYP2C9*1/*1 reference genotype.

10

°See ref [81] for further details on this issue.

11

References

[1] Sadler JE. Medicine: K is for koagulation. Nature. 2004;427(6974):493-4.

[2] Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon

and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227-46.

[3] Thijssen HH, Drittij MJ, Vervoort LM, de Vries-Hanje JC. Altered pharmacokinetics of R-

and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther.

2001;70(3):292-8.

[4] de Vries JX, Volker U. Determination of the plasma protein binding of the coumarin

anticoagulants phenprocoumon and its metabolites, warfarin and acenocoumarol, by

ultrafiltration and high-performance liquid chromatography. J Chromatogr. 1990;529(2):479-

85.

[5] Stehle S, Kirchheiner J, Lazar A, Fuhr U. Pharmacogenetics of oral anticoagulants: a basis

for dose individualization. Clin Pharmacokinet. 2008;47(9):565-94.

[6] Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and

foods. J Clin Pharmacol. 2005;45(2):127-32.

[7] Rost S, Fregin A, Koch D, Compes M, Muller CR, Oldenburg J. Compound heterozygous

mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all

vitamin K-dependent blood coagulation factors. Br J Haematol. 2004;126(4):546-9.

[8] Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med.

2005;353(10):1028-40.

[9] Troconiz IF, Tillmann C, Liesenfeld KH, Schafer HG, Stangier J. Population

pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR

1048) in patients undergoing primary elective total hip replacement surgery. J Clin

Pharmacol. 2007;47(3):371-82.

12

[10] Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro profile and ex-vivo

anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug,

dabigatran etexilate. Thromb Haemost. 2007;98(1):155-62.

[11] Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation.

2011;123(13):1436-50.

[12] Maegdefessel L, Linde T, Krapiec F, Hamilton K, Steinseifer U, van Ryn J, et al. In vitro

comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in

preventing thrombus formation on mechanical heart valves. Thromb Res.

2010;126(3):e196-200.

[13] Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van Ryn J. Dabigatran: an oral

novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol.

2010;30(10):1885-9.

[14] Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics,

pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin

inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292-303.

[15] Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the

direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet.

2008;47(1):47-59.

[16] van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran

etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation

assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-27.

[17] Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stahle H, et al. Pharmacokinetic

profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and

patients undergoing total hip replacement. J Clin Pharmacol. 2005;45(5):555-63.

13

[18] Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G, et al. Dose escalating

safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients

undergoing total hip replacement: BISTRO I. J Thromb Haemost. 2004;2(9):1573-80.

[19] Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the

pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label,

parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-68.

[20] Di Minno G, Russolillo A, Gambacorta C, Di Minno A, Prisco D. Improving the use of direct

oral anticoagulants in atrial fibrillation. Eur J Intern Med. 2013;24(4):288-94.

[21] Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of

dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos.

2010;38(9):1567-75.

[22] Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and

pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not

affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411-9.

[23] Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and clinical characteristics of

rivaroxaban: a novel, oral, direct factor Xa inhibitor. Semin Thromb Hemost.

2007;33(5):515-23.

[24] Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer KH, et al. In

vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct

Factor Xa inhibitor. J Thromb Haemost. 2005;3(3):514-21.

[25] Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics

of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet.

2009;48(1):1-22.

[26] Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and

pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin.

2008;24(10):2757-65.

14

[27] Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and

pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing

in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873-80.

[28] Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2

antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor

Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5):549-58.

[29] Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. Effect of hepatic

impairment on the pharmacokinetics and pharmacodynamics of a single dose of

rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89-98.

[30] Kubitza D, Becka M, Roth A, Mueck W. The influence of age and gender on the

pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct Factor Xa

inhibitor. J Clin Pharmacol. 2013;53(3):249-55.

[31] Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the

safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939)

in healthy subjects. J Clin Pharmacol. 2007;47(2):218-26.

[32] Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban:

population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis

and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin

Pharmacokinet. 2011;50(10):675-86.

[33] Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, et al. Effects of renal

impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an

oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703-12.

[34] Jiang J, Hu Y, Zhang J, Yang J, Mueck W, Kubitza D, et al. Safety, pharmacokinetics and

pharmacodynamics of single doses of rivaroxaban - an oral, direct factor Xa inhibitor - in

elderly Chinese subjects. Thromb Haemost. 2010;103(1):234-41.

15

[35] Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism.

Arterioscler Thromb Vasc Biol. 2008;28(3):380-6.

[36] Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban, an oral, direct

factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug

Metab Dispos. 2009;37(5):1046-55.

[37] Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally

bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31(4):478-92.

[38] Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor

Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost.

2010;104(6):1263-71.

[39] He K, Luettgen JM, Zhang D, He B, Grace JE, Jr., Xin B, et al. Preclinical pharmacokinetics

and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug

Metab Pharmacokinet. 2011;36(3):129-39.

[40] Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of

apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J

Thromb Haemost. 2008;6(10):1736-41.

[41] Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, Smallwood A, et al. Discovery of 1-

(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H -

pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective,

efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem.

2007;50(22):5339-56.

[42] Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al. Apixaban metabolism

and pharmacokinetics after oral administration to humans. Drug Metab Dispos.

2009;37(1):74-81.

[43] Prom R, Spinler SA. The role of apixaban for venous and arterial thromboembolic disease.

Ann Pharmacother. 2011;45(10):1262-83.

16

[44] De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral

anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on

Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. J Am Coll

Cardiol. 2012;59(16):1413-25.

[45] Upreti VV, Wang J, Barrett YC, Byon W, Boyd RA, Pursley J, et al. Effect of extremes of

body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of

apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76(6):908-16.

[46] Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, et al. Safety, pharmacokinetics

and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy

subjects. Br J Clin Pharmacol. 2013;76(5):776-86.

[47] Wang L, Zhang D, Raghavan N, Yao M, Ma L, Frost CE, et al. In vitro assessment of

metabolic drug-drug interaction potential of apixaban through cytochrome P450

phenotyping, inhibition, and induction studies. Drug Metab Dispos. 2010;38(3):448-58.

[48] Zafar MU, Vorchheimer DA, Gaztanaga J, Velez M, Yadegar D, Moreno PR, et al.

Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct

factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost. 2007;98(4):883-8.

[49] Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, et al. Clinical

safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa

inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743-53.

[50] Zahir H, Matsushima N, Halim AB, He L, Zhang G, Lee F, et al. Edoxaban administration

following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in

human subjects. Thromb Haemost. 2012;108(1):166-75.

[51] Mendell J, Zahir H, Matsushima N, Noveck R, Lee F, Chen S, et al. Drug-drug interaction

studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the

pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs.

2013;13(5):331-42.

17

[52] Parasrampuria DA, Marbury T, Matsushima N, Chen S, Wickremasingha PK, He L, et al.

Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects

undergoing haemodialysis. Thromb Haemost. 2015;113(4):719-27.

[53] Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of

edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol.

2011;51(5):687-94.

[54] Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics,

biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in

humans. Drug Metab Dispos. 2012;40(12):2250-5.

[55] Bounameaux H, Camm AJ. Edoxaban: an update on the new oral direct factor Xa inhibitor.

Drugs. 2014;74(11):1209-31.

[56] Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome

P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet.

1999;353(9154):717-9.

[57] Chan E, McLachlan AJ, Pegg M, MacKay AD, Cole RB, Rowland M. Disposition of warfarin

enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin

Pharmacol. 1994;37(6):563-9.

[58] Haustein KO. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants,

especially phenprocoumon. Semin Thromb Hemost. 1999;25(1):5-11.

[59] Thijssen HH, Verkooijen IW, Frank HL. The possession of the CYP2C9*3 allele is

associated with low dose requirement of acenocoumarol. Pharmacogenetics.

2000;10(8):757-60.

[60] Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and

practical considerations. Eur J Clin Pharmacol. 2013;69(9):1617-33.

[61] Thijssen HH, Hamulyak K, Willigers H. 4-Hydroxycoumarin oral anticoagulants:

pharmacokinetics-response relationship. Thromb Haemost. 1988;60(1):35-8.

18

[62] Cheng JW, Barillari G. Non-vitamin K antagonist oral anticoagulants in cardiovascular

disease management: evidence and unanswered questions. J Clin Pharm Ther.

2014;39(2):118-35.

[63] Parasrampuria DA, Weilert D, Maa JF, Dishy V, Kochan J, Shi M, et al. Pharmacokinetics

and Pharmacodynamics of the Nonvitamin K Antagonist Oral Anticoagulant Edoxaban

When Administered Alone or After Switching from Rivaroxaban or Dabigatran Etexilate in

Healthy Subjects. Clin Drug Investig. 2016;36(2):127-36.

[64] Hewick DS, McEwen J. Plasma half-lives, plasma metabolites and anticoagulant efficacies

of the enantiomers of warfarin in man. J Pharm Pharmacol. 1973;25(6):458-65.

[65] Comerota AJ, Ramacciotti E. A Comprehensive Overview of Direct Oral Anticoagulants for

the Management of Venous Thromboembolism. Am J Med Sci. 2016;352(1):92-106.

[66] Wang Y, Bajorek B. New oral anticoagulants in practice: pharmacological and practical

considerations. Am J Cardiovasc Drugs. 2014;14(3):175-89.

[67] Parasrampuria DA, Truitt KE. Pharmacokinetics and Pharmacodynamics of Edoxaban, a

Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa. Clin

Pharmacokinet. 2016;55(6):641-55.

[68] Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K

antagonists. Clin Pharmacokinet. 2013;52(2):69-82.

[69] www.drugbank.ca

[70] Kelly JG, O'Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet.

1979;4(1):1-15.

[71] Jahnchen E, Meinertz T, Gilfrich HJ, Groth U, Martini A. The enantiomers of

phenprocoumon: pharmacodynamic and pharmacokinetic studies. Clin Pharmacol Ther.

1976;20(3):342-9.

19

[72] Dieterle W, Faigle JW, Montigel C, Sulc M, Theobald W. Biotransformation and

pharmacokinetics of acenocoumarol (Sintrom) in man. Eur J Clin Pharmacol.

1977;11(5):367-75.

[73] Cui Y, Song Y, Wang J, Yu Z, Schuster A, Barrett YC, et al. Single- and multiple-dose

pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects.

Clin Pharmacol. 2013;5:177-84.

[74] Poulsen BK, Grove EL, Husted SE. New oral anticoagulants: a review of the literature with

particular emphasis on patients with impaired renal function. Drugs. 2012;72(13):1739-53.

[75] Beinema M, Brouwers JR, Schalekamp T, Wilffert B. Pharmacogenetic differences between

warfarin, acenocoumarol and phenprocoumon. Thromb Haemost. 2008;100(6):1052-7.

[76] Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Terleira-Fernandez AI, Vargas-Castrillon

E. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent

Pat Cardiovasc Drug Discov. 2014;9(1):2-10.

[77] Self TH, Wallace JL, Sakaan S, Sands CW. Effect of Body Weight on Dose of Vitamin K

Antagonists. South Med J. 2015;108(10):637-43.

[78] Russmann S, Gohlke-Barwolf C, Jahnchen E, Trenk D, Roskamm H. Age-dependent

differences in the anticoagulant effect of phenprocoumon in patients after heart valve

surgery. Eur J Clin Pharmacol. 1997;52(1):31-5.

[79] Cesar JM, Garcia-Avello A, Navarro JL, Herraez MV. Aging and oral anticoagulant therapy

using acenocoumarol. Blood Coagul Fibrinolysis. 2004;15(8):673-6.

[80] Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and

pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7):549-61.

[81] Hartter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate

(Pradaxa((R)) ) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol.

2013;75(4):1053-62.

20