Clinical pharmacology of DOACs

byAbdelwahab Ward, BS Pharm, PharmD - last updated
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MECHANISM OF ACTION ã…¡ Direct Oral Anticoagulants (DOACs) or Non-Vitamin K Antagonist Oral Anticoagulant (NOACs) are Direct Thrombin Inhibitors (e.g., Dabigatran) and Factor Xa Inhibitors (e.g. Rivaroxaban, Apixaban, Edoxaban) with prothrombinase activity, thus inhibiting the conversion of prothrombin to thrombin (see Figure 1).

          Thrombin catalyzes the conversion of fibrinogen to fibrin; activates factors V, VIII, XI, and XIII; and activates platelets. Therefore, inhibiting thrombin decreases thrombus formation. Routine therapeutic monitoring was not done in the major DOAC efficacy trials and is at present not recommended in usual clinical practice.

INDICATIONS AND DOSAGE

In general, FDA‐approved indications and doses for each of the DOACs are comparable (see Table 1). Dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) are approved for the lowering the risk of stroke and embolism in NVAF as well as deep vein thrombosis and pulmonary embolism treatment/prophylaxis. Apixaban (Eliquis) can be used for treatment of heparin‐induced thrombocytopenia.

Table (1). Comparison Among DOACs
Dabigatran Rivaroxaban Apixaban Edoxaban
Approved indications Nonvalular AF 
↓ Risk of stroke and systemic embolism		 Nonvalular AF 
↓ Risk of stroke and systemic embolism		 Nonvalular AF 
↓ Risk of stroke and systemic embolism		 Nonvalular AF 
↓ Risk of stroke and systemic embolism.Limitation: should not use in patients with CrCl >95 mL/min as a result of ↑ risk of ischemic stroke compared with warfarin at 60 mg
DVT, PE Treatment after 5–10 d parenteral AC 
↓ Recurrence Prophylaxis after hip replacement		 DVT, PE Treatment 
↓ Recurrence Prophylaxis after hip or knee replacement		 DVT, PE Treatment 
↓ Recurrence Prophylaxis after hip replacement		 DVT, PE 
↓ Recurrence Treatment after 5–10 d initial parenteral AC
Mechanism of action Direct thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor
Time to peak 1 h; delayed to 2 h with food 2–4 h 3–4 h 1–2 h
Bioavailability 3%–7% 10-mg dose: 80%–100% ~50% 62%
20-mg dose: 66%
↑ With food
Plasma protein binding 35% 92%–95% ~87% 55%
Volume of distribution 50–70 L 50 L 21 L 107 L
Plasma t1/2 12–17 h 5–9 h ~12 h (8–15 h) 10–14 h
Elderly 14–17 h Elderly 11–13 h
Mild to moderate renal impairment 15–18 h
Severe renal impairment 28 h
Metabolism Hepatic and plasma hydrolysis to active dabigatran Hepatic: oxidation by CYP3A4/5, CYP2J2; hydrolysis to inactive metabolites (51%) Hepatic: 25% mainly by CYP3A4/5; lesser by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2; O-demethylation and hydroxylation Minimal CYP3A4 hydrolysis, conjugation, oxidation
Hepatic glucuronidation to active metabolites (<10%) P-gp substrate No active circulating metabolites Active metabolite (M-4, <10% of parent)
P-gp substrate No major or active circulating metabolites Substrate of CYP3A4, P-gp, BCRP P-gp substrate
Substrate of P-gp and ABCG2 (BCRP)
Excretion Renal (~80%) after IV administration Renal (66%): 36% active, 30% inactive metabolites Renal (27%) Renal (~50%): primarily as unchanged drug
After oral, 7% recovered in urine, 86% in feces Feces (28%): 7% active, 21% inactive metabolites Biliary and direct intestinal excretion Metabolism and biliary/intestinal excretion accounts for the rest
Dosing
Nonvalvular AF CrCl >30 mL/min: 150 mg BID CrCl >50 mL/min: 20 mg daily with evening meal 5 mg BID CrCl >50 to ≤95 mL/min: 60 mg daily
CrCl 15–30 mL/min: 75 mg BID CrCl 15–50 mL/min: 15 mg daily with evening meal 2.5 mg BID, if 2 of 3 characteristics: Cr ≥1.5 mg/dL, age ≥80 y, weight ≤60 kg CrCl 15–50 mL/min: 30 mg daily
CrCl <15 mL/min or on dialysis: Not recommended Not recommended for CrCl <15 mL/min or on dialysis in patients with AF NOT recommended for CrCl >95 mL/min
CrCl 30–50 mL/min with concomitant P-gp inhibitors: 75 mg BID
CrCl <30 mL/min with concomitant P-gp inhibitors: Avoid coadministration
DVT or PE treatment CrCl >30 mL/min: 150 mg BID after 5-10 d parenteral anticoagulation 15 mg BID with food first 21 d for initial treatment, then 20 mg once daily with food 10 mg BID x 7 d, then 5 mg BID 60 mg once daily
CrCl ≤30 mL/min or on dialysis: Not recommended Not recommended for CrCl <30 mL/min in patients with DVT or PE CrCl 15–50 mL/min or weight ≤60 kg or on certain P-gp inhibitors: 30 mg once daily
↓ in recurrent DVT/PE CrCl >30 mL/min: 150 mg BID after 5–10 d parenteral anticoagulation 20 mg daily with food 2.5 mg BID
CrCl ≤30 mL/min or on dialysis: Not recommended
DVT, PE prophylaxis after hip or knee replacement After hip replacement surgery:CrCl >30 mL/min after achievement of hemostasis: If given day of surgery, 110 mg 1–4 h postop; after day of surgery 220 mg once daily x 28–35 dCrCl ≤30 mL/min or on dialysis: Not recommendedCrCl <50 mL/min with concomitant P-gp inhibitors: Avoid coadministration Initial dose 6–10 h after surgery provided hemostasis established 2.5 mg BID x 35 d after hip replacement surgery or x 12 d after knee replacement surgery
10 mg daily with or without food x 35 d for hip replacement, x 12 d for knee replacement
Additional dosing comments Avoid use with patients with moderate-severe hepatic impairment (Child-Pugh class B/C) or hepatic disease with coagulopathy Not recommended in patients with severe hepatic impairment (Child-Pugh class C) Not recommended with CrCl <15 mL/min
15-20 mg taken with food; 10 mg with or without food Not recommended in patients with moderate-severe hepatic impairment (Child-Pugh class B/C)
Therapeutic measurement Routine not required Routine not required Routine not required Routine not required
To detect presence: aPTT, ECT (if available), TT To detect presence: PT, aPTT, antifactor Xa activity To detect presence: PT, aPTT, antifactor Xa activity Prolongs PT, aPTT, antifactor Xa activity
aPTT >2.5 times control may indicate overanticoagulation Renal function, CBC periodically, at least annually; hepatic function Renal function, CBC periodically, at least annually Renal function, CBC periodically, at least annually
Renal function, CBC periodically, at least annually
AC indicates anticoagulant; AF, atrial fibrillation; aPTT, activated partial thromboplastin time; BID, twice daily; CBC, complete blood count; CrCl, creatinine clearance; DVT, deep vein thrombosis; ECT, ecarin clotting time; IV, intravenous; NOACs, non–vitamin K antagonist oral anticoagulants; PE, pulmonary embolism; P-gp, P-glycoprotein; PT, prothrombin time; and TT, thrombin time.

DRUG INTERACTION

Direct oral anticoagulants (e.g. Dabigatran, Rivaroxaban) also have significant drug interactions. You should review specific agents for drug interactions (e.g., P-glycoprotein, CYP3A4). Highest risk agent are ketoconazole, fluconazole, ritonavir, amiodarone. Unknown safety and bleeding risk when combined with antiplatelet agents. Reducing DOAC dose due to drug interaction risk may render it ineffective.

          Macrolides and nondihydropyridine calcium channel blockers are 2 commonly prescribed classes of medications that impact therapeutic levels of NOACs, although a post hoc analysis of ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) showed no evidence of differential outcomes between rivaroxaban and warfarin in patients treated with ≥1 combined P-gp and CYP 3A4 inhibitors. Edoxaban exists in a predominantly unchanged form in plasma with minimal metabolism through hydrolysis, conjugation, and oxidation by CYP 3A4.

Table (2). DOAC Drug Interactions
DOAC Interacting Medications Effect on NOAC Labeled Guidance; Comments
Dabigatran P-gp inducer: rifampin ↓ Dabigatran exposure Concomitant use should generally be avoided.
P-gp inhibitors: ketoconazole, dronedarone ↑ Dabigatran exposure if concomitant moderate renal impairment If moderate renal impairment (CrCl 30–50 mL/min) ↓ to 75 mg BID during concomitant use
P-gp inhibitors: ketoconazole, dronedarone, verapamil, amiodarone, quinidine, clarithromycin, ticagrelor ↑ Dabigatran exposure if concomitant severe renal impairment If severe renal impairment (CrCl 15–30 mL/min) avoid concomitant use
Apixaban Strong dual P-gp and CYP3A4 inducers: rifampin, carbamazepine, phenytoin, St. John’s wort ↓ Apixaban exposure Avoid concomitant use
Strong dual P-gp and CYP3A4 inhibitors: ketoconazole, itraconazole, ritonavir, clarithromycin ↑ Apixaban exposure In patients on 5 mg or 10 mg BID, ↓ dose by 50% when coadministered
Avoid coadministration on 2.5 mg BID
Rivaroxaban Combined P-gp and strong CYP3A4 inducers: rifampin, carbamazepine, phenytoin, St. John’s wort ↓ Rivaroxaban exposure Avoid concomitant use; may decrease rivaroxaban efficacy
Combined P-gp and strong CYP3A4 inhibitors: ketoconazole, itraconazole, HIV protease inhibitors (ritonavir, lopinavir/ritonavir, indinavir), conivaptan ↑ Rivaroxaban exposure Avoid concomitant use
Combined P-gp and moderate CYP3A4 inhibitors: diltiazem, verapamil, amiodarone, dronedarone, erythromycin ↑ Rivaroxaban exposure in patients with renal impairment In patients with CrCl 15 to <80 mL/min, rivaroxaban should not be used concomitantly unless the potential benefit justifies the potential risks
No evidence of interaction observed in ROCKET AF between treatment assignment and outcomes in patients using ≥1 combined P-gp and moderate 3A4 inhibitors (including amiodarone, diltiazem, and verapamil)
Edoxaban P-gp inducer: rifampin ↓ Edoxaban exposure Avoid concomitant use
Strong P-gp inhibitors: ritonavir, nelfinavir, saquinavir, indinavir, cyclosporine ↑ Edoxaban exposure Avoid concomitant use in patients taking edoxaban for treatment of VTE
P-gp inhibitors: verapamil, quinidine, azithromycin, clarithromycin, itraconazole, ketoconazole ↑ Edoxaban exposure ↓ to 30 mg daily during concomitant administration for patients taking edoxaban for the treatment of VTE
Dose reduction is not recommended for AF indications
In ENGAGE AF, a ↓ dose of edoxaban as a result of concomitant P-gp inhibitor use (verapamil, quinidine, dronedarone) was associated with ↓ edoxaban exposure and a relative ↑ in risk of stroke or systemic embolism with edoxaban relative to warfarin
AF, atrial fibrillation; BID, twice daily; CrCl, creatinine clearance; ENGAGE AF, Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation trial; NOAC, non–vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein; ROCKET AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; and VTE, venous thromboembolism.

REFERENCES

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