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

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

PK and PD rivaroxaban apixaban edoxaban dabigatran 3

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) 0.5-2.0 2.0-4.0 3.0-4.0 1.0-2.0 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

Dabigatran concentrations and bleeding risk

Edoxaban concentrations and bleeding risk

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

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®

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®

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®

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®

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®

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

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®

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®

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 15-29 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 50-100 kg group No dose adjustement required 30% reduction of the exposure No information Eu-SmPC Pradaxa® Xarelto® Eliquis® Lixiana®

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

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 15-29 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.

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. 2010.

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. 2015.

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., rs2244613 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

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

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

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

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

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

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?

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

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)

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

Thank you for your attention