1. The role of PK and PD measurements in the era of DOACs
Jonathan DOUXFILS
Department of pharmacy
Faculty of Medicine
University of Namur

2. Content Context Monitoring/point measurement Why to measure?
When to measure?
How to measure?

3. PK and PD
rivaroxaban
apixaban
edoxaban
dabigatran 3

4. PK and PD dabigatran etexilate (PRADAXA®) rivaroxaban (XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
Target
Thrombin
Factor Xa
Bioavailability (%)
3-7%
Not affected by food
80 to 100% for the 10 mg
66% for the 15 and 20 mg (fasted)*
50%
62%
Prodrug
Yes – activated by esterase (CES1) No
Half-life (hours)
11-13
5-13
8-15
10-14
TMAX (hours)
Renal clearance
80%
33%
25%
Metabolism
P-gp
CYP3A4
CYP3A4/5, 1A2, 2J2
CYP3A4/5
* these dose regimen have to be taken with food. 4

5. Dabigatran concentrations and bleeding risk

6. Edoxaban concentrations and bleeding risk

7. Content Context Monitoring/point measurement Why to measure?
When to measure?
How to measure?

8. WHY TO MEASURE? Drug interactions
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
Anti-H2/proton pump inhibitors
30% reduction of the AUC
No impact on efficacy in RCT
No impact
Eu-SmPC Pradaxa® Xarelto® Eliquis® Lixiana®

9. Drug interactions dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
Strong P-gp inhibitors
Contraindicated
Moderated P-gp inhibitors
Caution!
Strong P-gp inducers
Ketoconazole
Itraconazole
Dronédarone
Ciclosporine
Tacrolimus
Amiodarone
Verapamil
Quinidine
Clarithromycin
Rifampicin
St John’s wort
Carbamazepine
Phenytoin
+ PD interactions
ASA
Clopidogrel
NSAIDs
SSRI and SNERI
Concomitant treatment with other anticoagulant CI
Dose tailoring:
VTE prevention post TKR/THR: max 150 mg/day (2 caps of 75 mg od)
SPAF: max 220 mg/day (1 caps 110 mg bid)
Eu-SmPC Pradaxa®

10. Drug interactions rivaroxaban
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
Strong P-gp and CYP3A4 inhibitors
Not-recommended
Moderated P-gp inhibitors
Caution!
Strong P-gp inducers
Ketoconazole
Itraconazole
Voriconazole
Posaconazole
Protease inhibitors (ritonavir,…)
Clarithromycin
Erythromycin
Rifampicin
St John’s wort
Carbamazepine
Phenytoin
Phenobarbital
+ PD interactions
ASA
Clopidogrel
NSAIDs
SSRI and SNERI
Concomitant treatment with other anticoagulant CI
No dose adjustment
Eu-SmPC Xarelto®

11. Drug interactions apixaban
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
Strong P-gp and CYP3A4 inhibitors
Not-recommended
Moderated P-gp inhibitors
Caution!
Strong P-gp inducers
Ketoconazole
Itraconazole
Voriconazole
Posaconazole
Protease inhibitors (ritonavir,…) /
Rifampicin
St John’s wort
Carbamazepine
Phenytoin
Phenobarbital
+ PD interactions
ASA
Clopidogrel
NSAIDs
SSRI and SNERI
Concomitant treatment with other anticoagulant CI
No dose adjustment
Eu-SmPC Eliquis®

12. Drug interactions edoxaban
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
P-gp and CYP3A4 inhibitors
Dose reduction
Other P-gp and CYP3A4 inhibitors
Caution!
Strong P-gp inducers
Cyclosporine
Dronedarone
Erythromycin
Ketoconazole
Amiodarone
Verapamil
Quinidine
Rifampicin
St John’s wort
Carbamazepine
Phenytoin
Phenobarbital
+ PD interactions
ASA
Clopidogrel
NSAIDs
SSRI and SNERI
Concomitant treatment with other anticoagulant CI
SPAF and DVT/PE:
- edoxaban 30 mg od
No dose adjustment
Eu-SmPC Lixiana®

13. Drug interactions unknown drug interactions
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
CYP substrate 
 3A4, 2J2 + cyp-independent mechanism
3A4/5, 1A2, 2J2 + cyp-independent mechanism
 3A4/5 + cyp-independent mechanism
Transport substrate
 P-gp
Strong P-gp and CYP3A4 inhibitors
Moderated P-gp and CYP3A4 inhibitors
Strong P-gp and CYP3A4 inducers
Not recommended
if requested:
Clinical monitoring
Biological tests?
Caution
Risk of underdosing
+ PD interactions
ASA
Clopidogrel
dypiridamol,etc…
Concomitant treatment with other anticoagulant
Assessment of the B/R balance CI
Following regional availability, a consultation with a coagulation specialist has to be envisaged in case of bleeding or recurrence of thrombosis

14. WHY TO MEASURE? Renal impairment
Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment with DOACs
Several dosing recommendations based on CrCl
Algorythm for the monitoring of the renal function has been proposed*
 CrCl divided by 10 if CrCl is below 60 mL/min
* There are several proposals for the monitoring of the kidney function, but in any case, yearly monitoring is probably not sufficient in patients with impaired renal function.
Heidbuchel H, et al. Europace: 2015.
Eu-SmPC Pradaxa® Xarelto® Eliquis® and Lixiana®

15. WHY TO MEASURE? Hepatic impairment
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
Hepatic disease associated with coagulopathy
CONTRINDICATED
 Recommendation:
Prior to initiating DOACs, liver function testing should be performed.
Heidbuchel H, et al. Europace: 2015.
Eu-SmPC Pradaxa® Xarelto® Eliquis® Lixiana®

16. WHY TO MEASURE? Extreme body weight
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
Low body weight (<50-60 kg)
No dose adjustment required
Limited clinical data are available for patients <50 kg
Variation of less than 25% of the exposure
Dose reduction: 2.5 mg bid
if at least 2 of the following:
≥80 years
≤60 kg
serum creat. ≥ 1,5 mg/dl or if CrCl ml/min
30 % increase of the exposure
Dose reduction: 30 mg od
CMAX and AUC increased by 40% and 13%, respectively
High body weight (>120 kg)
Trough dabigatran concentrations were 20% lower in patients >100 kg compared to the kg group
No dose adjustement required
30% reduction of the exposure
No information
Eu-SmPC Pradaxa® Xarelto® Eliquis® Lixiana®

17. Extreme body weight Guidance from the SSC of the ISTH
appropriate standard dosing of the DOACs in patients with a BMI less than or equal to 40 kg/m2 and weight less than or equal to 120 kg
DOACs should not be used in patients with a BMI of > 40 kg/m2 or a weight of > 120 kg, PK/PD evidence raises concerns about underdosing in the population at the extreme of weight.
If DOACs are used in a patient with a BMI of > 40 kg/m2 or a weight of > 120 kg, checking a drug-specific peak and trough level.
Martin et al. Journal of Thrombosis and Haemostasis. 2016

18. WHY TO MEASURE? Other special populations
dabigatran etexilate
(PRADAXA®)
rivaroxaban
(XARELTO®)
apixaban
(ELIQUIS®)
edoxaban
(LIXIANA®)
Elderly
Patients aged 80 years or above should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily due to the increased risk of bleeding in this population.
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No
dose adjustment is necessary.
Dose reduction: 2.5 mg bid
if at least 2 of the following:
≥80 years
≤60 kg
serum creat. ≥ 1,5 mg/dl or if CrCl ml/min
Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in CMAX.
After taking renal function and body weight into account, age had no additionnal clinically significant effect on edoxaban pharmacokinetics
Ethnic origin
and race
No clinically relevant ethnic differences.
However, 32.8% of the white European participants of the RE-LY study presented a particular SNP that decreased trough concentrations to the rate of the 110mg BID dose
No clinically relevant inter-ethnic differences
No clinically relevant inter-ethnic differences.

19. KEY QUESTION… Pro or cons monitoring?
PK-PD studies: preditable response
All RCT were performed without monitoring
Large therapeutic range
Bounameaux H, Reber G. JTH

20. KEY QUESTION… Pro or cons monitoring?
Reilly PA et al., JACC. 2013; Ruff et al., The Lancet. 2015; Douxfils et al., Exp. Op. Drug Saf

21. Patients or situations requiring an assessment of the response
Bleeding or recurrence of thrombosis
Before an invasive procedure (elective or urgent surgery)
Laboratory vs pharmacokinetic approach
In patients with potential drug interactions that affect the pharmacokinetics of DOACs
In patients with extreme body weight (< 50 or > 100 kg)
In elderly patients (> 75 years of age)
In patients with genetic mutations (i.e., rs minor allele carriers for dabigatran etexilate)
In case of accumulating interfering factors
Douxfils et al. Exp. Op. Drug. Saf. 2015; Reiffel et al. Am Heart J 2016; Tripodi et al. JTH 2016; Spyropoulos et al. JTH 2016

22. Can we use routine PT or aPTT?
PT and APTT are not adequate methods to detect low levels of DOAC and do not appropriately correlate with plasma levels
Gosselin et al. Journal of Thrombosis and Haemostasis. 2015; Douxfils et al. TrAC. 2016

23. Assays available to measure plasma levels of the DOACs
Weitz et al. Circulation 2016

24. Implementation in routine care setting
Most automated coagulation instruments can perform TT, dTT, ecarin-based assays and chromogenic anti-Xa assays
CE approved
Median TAT of 34 min in a stroke unit demonstrates that rapid measurement is feasible if routinely implemented
Gosselin et al. Journal of Thrombosis and Haemostasis. 2015; Douxfils et al. TrAC. 2016; Seiffge et al. JTT. 2016

25. Which tests?
Note: adapted methodology may be required for specific tests due to the LOQ
Douxfils et al. JTH. To be submitted soon…

26. Which tests?
Note: adapted methodology may be required for specific tests due to the LOQ
Douxfils et al. JTH. To be submitted soon…

27. Limitations of current measurements
Inter-laboratory variation
Implementation of international standards for calibration
Turn-around time in emergent situations if not implemented in routine
Are plasma levels the good biomarker to assess the individual response of the patient? Can we get more information from global assays such thrombin generation test/thromboelastography?

28. PERSPECTIVES What do we need in the future?
NOW…
DOACs are now cornerstones in the treatment of various thromboembolic diseases but several situations may require the use of coagulation testing
Specific tests are more suitable but still not easy to implement
Mainly due to position of regulatory bodies (in the US)
BUT, on a technical point of view, they can be implemented in routine and cost around 15 to 30€ per test

29. PERSPECTIVES What do we need in the future?
FUTURE can be…
Determination of plasma concentration is feasible but safe threshold have to be clearly established for all DOAC
depending on the population
Proposals of cut-off for safe surgery have to be confirmed in prospective studies
Identify those that may benefit from specific dose tailoring
Development of (new) tests…
able to provide individualized response to the treatment, not only measuring plasma levels (inter-individual variation of plasma protein levels, contribution of antiplatelet agents,…)
able to guide the physician in emergent situations (POC device)

30. Acknowledgments Prof. Jean-Michel Dogné Prof. François Mullier
Prof. Bernard Chatelain
Technical staff of the CHU UCL Namur and the University of Namur
A faire

31. Thank you for your attention