Opinion
VIEWPOINT
J. Robert Powell, PharmD Eshelman School of Pharmacy, University of North Carolina, Chapel Hill.
Corresponding Author: Robert J. Powell, PharmD, Eshelman School of Pharmacy, University of North Carolina, 301 Pharmacy Ln, Chapel Hill, NC 27599-7355 (bob.powell49@gmail .com).
Are New Oral Anticoagulant Dosing Recommendations Optimal for All Patients? from the phase 3 trials, dabigatran and rivaroxaban appear to be similar.4 Apixaban plasma concentration variability has not been reported.5 According to information from the manufacturer of dabigatran, Boehringer Ingelheim, there is a high likelihood that adjusted individualized dosing for dabigatran, with a target range for plasma drug concentration of 40 ng/mL to 200 ng/mL, is safer (associated with fewer major bleeding events) and as effective compared with 150 mg dabigatran twice daily for all patients without dose adjustment. These internal analyses and communications have recently been published.6,7 The FDA seems to agree with this view. In reviewing the edoxaban New Drug Application (October 30, 2014), the FDA medical officer concluded that “we should start considering exposure targeting to maximize the benefit-risk profile of [new oral anticoagulants].”8 The FDA suggested that these drugs could be potentially more efficacious and safer if dose adjustment to meet individual needs were used. It is possible to determine if DOAC dose adjustment is worthwhile. Individualized DOAC dosing may benefit drugs with greater interpatient variability in pharmacokinetics or pharEven though the one-size-fits-all DOAC macodynamics, patients who do not have average characteristics (eg, those dosing may perform as well as or better with extremes of age, weight, or organ than warfarin on average… patient function), when other factors change (eg, safety can be further improved through rapid renal function change, new interacting drug), or when patients have mulindividualized patient dosing. tiple characteristics that could affect dosthe same strategy of 1 dose for all patients and no ing. It is unlikely pharmaceutical companies will move in need for laboratory testing. This is in part the market- this direction without FDA action. Without a serious posting profile each company used at the drug discovery market safety signal indicating that a DOAC has greater phase that then guided development decisions risk than warfarin, the FDA may not have authority to rethrough phase 3 trial design, execution, and New Drug quire an individualized dose regimen. Application submission. Consequently, the FDA deciOne path forward is for the FDA or the European sions to approve the drugs and the labeled dosing Medicines Agency to make the individual patient data guidelines usually conform to those used in the piv- from phase 2-3 clinical trials available (all DOACs) for otal phase 3 trials. modeling and clinical trial simulations, such as those Large variability in drug plasma concentration is performed by Boehringer Ingelheim. These data sets, not a desirable characteristic for an agent with a nar- which comprise 5000 to 10 000 patients per treatrow therapeutic index, for which the risks of underdos- ment group, are an important source of information age or overdosage include death and severe morbidity. required to distinguish low-frequency, high-risk Anticoagulants, including DOACs, have intrinsically changes in morbidity and mortality. Data such as these narrow therapeutic indices. The phase 3 clinical trial for are unlikely to be replicated soon. Model-based metadabigatran, the RE-LY trial, reported a 400-fold inter- analysis using individual-patient data could allow a patient difference at peak plasma concentration and a more precise, quantitative understanding of drug, dos700-fold difference at trough drug concentration.2 A age, individual patient characteristics, and outcomes possible explanation for this high patient variability is (therapeutic, toxic). From these models, new dosing the reported 3% to 6.5% fraction of the dose recommendations could be constructed and tested by absorbed or bioavailability.3 Although it is difficult to clinical trial simulations to better understand which find data on interpatient and intrapatient variability patients will benefit most from dose individualization. The ability to understand how to optimally achieve anticoagulation with warfarin took 60 years since its approval by the US Food and Drug Administration (FDA) in 1954. How long will it take clinicians to understand how to optimally dose the new thrombin and factor Xa inhibitors in all patients? The rapidly emerging new direct-acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have been found noninferior or superior to individualized warfarin dosing in preventing stroke, while causing similar or less risk of hemorrhage.1 These drugs have several common features: 1 dose for all patients (age, renal function adjustments), no need for routine laboratory testing, rapid onset and decay of anticoagulant activity when dosing is started and stopped, and fewer interactions (eg, with food or drugs). Even though the one-size-fits-all DOAC dosing may perform as well as or better than warfarin on average, evidence suggests that patient safety can be further improved through individualized dosing. It is not a coincidence that 3 US-marketed DOACs share
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(Reprinted) JAMA March 10, 2015 Volume 313, Number 10
Copyright 2015 American Medical Association. All rights reserved.
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1013
Opinion Viewpoint
A therapeutic range (ie, drug concentration, clotting test) and dosing schemes could be created for factors (eg, renal function) likely to cause patients to be outside this range. Using the prior phase 3 database for each drug, simulations could be used to estimate performance differences in outcomes compared with the current fixed dosing regimen. This work may begin to show which patients would benefit most from individualized dosing. A biomarker test (drug concentration or clotting assay) will require both regulatory and commercial development. The FDA has expressed a willingness to adapt dosing recommendations for dabigatran and edoxaban based on modeling and simulation within the clinical trial experiences.9 Alternatively, if the prior clinical trial experience cannot be made available, therapeutic ranges and dosing schemes could still be constructed based on the current literature. However, these dosing schemes would need to be tested prospectively. This is likely to be a much longer and more expensive approach. Biomarker test feedback for dose adjustment would likely only be required when the drug is first prescribed and then when there ARTICLE INFORMATION Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. 2. Reilly PA, Lehr T, Haertter S, et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014; 63(4):321-328.
1014
is a significant change in the patient’s renal function or weight or an interacting drug is added. However, assessing a biomarker test (drug concentration or clotting assay) when a patient is first prescribed a DOAC represents less testing than with warfarin. This laboratory testing regimen was determined by Boehringer Ingelheim to be sufficient and has been proposed by the FDA.7 Without cooperation from the DOAC manufacturers, research funding for either path will require support from government and nonprofit organizations. Because 3 to 4 DOACs are now available, depending on the country, it may be feasible to coordinate research plans and funding between the United States, European Union, and Japan. Eventually, one DOAC will likely emerge as the market leader. However, additional research could create a more competitive market. It may be that dose individualization could decrease differences between drugs if they are titrated to a more common standard based on individual patient requirements. Greater assurance is needed so these new anticoagulants can be optimally dosed for all eligible patients.
3. Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther. 1996;60(6):601-607. 4. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol. 2014;54(8):917-927. 5. Kowalski K, Nielsen J, Roy A, et al. Apixaban exposure and anti-Xa activity in nonvalvular atrial fibrillation patients: an application of population PK/PD analysis. J Pharmacokinet Pharmacodyn. 2014;41:S19-S20.
http://journals.bmj.com/site/bmj/dabigatran /compared_ema.pdf. Accessed January 9, 2015. 8. US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee. Edoxaban NDA 206314: Statistical Considerations, ENGAGE AF Trial. FDA website. http://www.fda.gov/downloads /AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /CardiovascularandRenalDrugsAdvisoryCommittee /UCM421612.pdf. Accessed January 9, 2015. 9. Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011;364 (19):1788-1790.
6. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014;349:g4670. 7. An Idea for a Mid to Long Term Strategy for Pradaxa. Boehringer Ingelheim website.
JAMA March 10, 2015 Volume 313, Number 10 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/15/2015
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VIEWPOINT
J. Robert Powell, PharmD Eshelman School of Pharmacy, University of North Carolina, Chapel Hill.
Corresponding Author: Robert J. Powell, PharmD, Eshelman School of Pharmacy, University of North Carolina, 301 Pharmacy Ln, Chapel Hill, NC 27599-7355 (bob.powell49@gmail .com).
Are New Oral Anticoagulant Dosing Recommendations Optimal for All Patients? from the phase 3 trials, dabigatran and rivaroxaban appear to be similar.4 Apixaban plasma concentration variability has not been reported.5 According to information from the manufacturer of dabigatran, Boehringer Ingelheim, there is a high likelihood that adjusted individualized dosing for dabigatran, with a target range for plasma drug concentration of 40 ng/mL to 200 ng/mL, is safer (associated with fewer major bleeding events) and as effective compared with 150 mg dabigatran twice daily for all patients without dose adjustment. These internal analyses and communications have recently been published.6,7 The FDA seems to agree with this view. In reviewing the edoxaban New Drug Application (October 30, 2014), the FDA medical officer concluded that “we should start considering exposure targeting to maximize the benefit-risk profile of [new oral anticoagulants].”8 The FDA suggested that these drugs could be potentially more efficacious and safer if dose adjustment to meet individual needs were used. It is possible to determine if DOAC dose adjustment is worthwhile. Individualized DOAC dosing may benefit drugs with greater interpatient variability in pharmacokinetics or pharEven though the one-size-fits-all DOAC macodynamics, patients who do not have average characteristics (eg, those dosing may perform as well as or better with extremes of age, weight, or organ than warfarin on average… patient function), when other factors change (eg, safety can be further improved through rapid renal function change, new interacting drug), or when patients have mulindividualized patient dosing. tiple characteristics that could affect dosthe same strategy of 1 dose for all patients and no ing. It is unlikely pharmaceutical companies will move in need for laboratory testing. This is in part the market- this direction without FDA action. Without a serious posting profile each company used at the drug discovery market safety signal indicating that a DOAC has greater phase that then guided development decisions risk than warfarin, the FDA may not have authority to rethrough phase 3 trial design, execution, and New Drug quire an individualized dose regimen. Application submission. Consequently, the FDA deciOne path forward is for the FDA or the European sions to approve the drugs and the labeled dosing Medicines Agency to make the individual patient data guidelines usually conform to those used in the piv- from phase 2-3 clinical trials available (all DOACs) for otal phase 3 trials. modeling and clinical trial simulations, such as those Large variability in drug plasma concentration is performed by Boehringer Ingelheim. These data sets, not a desirable characteristic for an agent with a nar- which comprise 5000 to 10 000 patients per treatrow therapeutic index, for which the risks of underdos- ment group, are an important source of information age or overdosage include death and severe morbidity. required to distinguish low-frequency, high-risk Anticoagulants, including DOACs, have intrinsically changes in morbidity and mortality. Data such as these narrow therapeutic indices. The phase 3 clinical trial for are unlikely to be replicated soon. Model-based metadabigatran, the RE-LY trial, reported a 400-fold inter- analysis using individual-patient data could allow a patient difference at peak plasma concentration and a more precise, quantitative understanding of drug, dos700-fold difference at trough drug concentration.2 A age, individual patient characteristics, and outcomes possible explanation for this high patient variability is (therapeutic, toxic). From these models, new dosing the reported 3% to 6.5% fraction of the dose recommendations could be constructed and tested by absorbed or bioavailability.3 Although it is difficult to clinical trial simulations to better understand which find data on interpatient and intrapatient variability patients will benefit most from dose individualization. The ability to understand how to optimally achieve anticoagulation with warfarin took 60 years since its approval by the US Food and Drug Administration (FDA) in 1954. How long will it take clinicians to understand how to optimally dose the new thrombin and factor Xa inhibitors in all patients? The rapidly emerging new direct-acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have been found noninferior or superior to individualized warfarin dosing in preventing stroke, while causing similar or less risk of hemorrhage.1 These drugs have several common features: 1 dose for all patients (age, renal function adjustments), no need for routine laboratory testing, rapid onset and decay of anticoagulant activity when dosing is started and stopped, and fewer interactions (eg, with food or drugs). Even though the one-size-fits-all DOAC dosing may perform as well as or better than warfarin on average, evidence suggests that patient safety can be further improved through individualized dosing. It is not a coincidence that 3 US-marketed DOACs share
jama.com
(Reprinted) JAMA March 10, 2015 Volume 313, Number 10
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/15/2015
1013
Opinion Viewpoint
A therapeutic range (ie, drug concentration, clotting test) and dosing schemes could be created for factors (eg, renal function) likely to cause patients to be outside this range. Using the prior phase 3 database for each drug, simulations could be used to estimate performance differences in outcomes compared with the current fixed dosing regimen. This work may begin to show which patients would benefit most from individualized dosing. A biomarker test (drug concentration or clotting assay) will require both regulatory and commercial development. The FDA has expressed a willingness to adapt dosing recommendations for dabigatran and edoxaban based on modeling and simulation within the clinical trial experiences.9 Alternatively, if the prior clinical trial experience cannot be made available, therapeutic ranges and dosing schemes could still be constructed based on the current literature. However, these dosing schemes would need to be tested prospectively. This is likely to be a much longer and more expensive approach. Biomarker test feedback for dose adjustment would likely only be required when the drug is first prescribed and then when there ARTICLE INFORMATION Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. 2. Reilly PA, Lehr T, Haertter S, et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014; 63(4):321-328.
1014
is a significant change in the patient’s renal function or weight or an interacting drug is added. However, assessing a biomarker test (drug concentration or clotting assay) when a patient is first prescribed a DOAC represents less testing than with warfarin. This laboratory testing regimen was determined by Boehringer Ingelheim to be sufficient and has been proposed by the FDA.7 Without cooperation from the DOAC manufacturers, research funding for either path will require support from government and nonprofit organizations. Because 3 to 4 DOACs are now available, depending on the country, it may be feasible to coordinate research plans and funding between the United States, European Union, and Japan. Eventually, one DOAC will likely emerge as the market leader. However, additional research could create a more competitive market. It may be that dose individualization could decrease differences between drugs if they are titrated to a more common standard based on individual patient requirements. Greater assurance is needed so these new anticoagulants can be optimally dosed for all eligible patients.
3. Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther. 1996;60(6):601-607. 4. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol. 2014;54(8):917-927. 5. Kowalski K, Nielsen J, Roy A, et al. Apixaban exposure and anti-Xa activity in nonvalvular atrial fibrillation patients: an application of population PK/PD analysis. J Pharmacokinet Pharmacodyn. 2014;41:S19-S20.
http://journals.bmj.com/site/bmj/dabigatran /compared_ema.pdf. Accessed January 9, 2015. 8. US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee. Edoxaban NDA 206314: Statistical Considerations, ENGAGE AF Trial. FDA website. http://www.fda.gov/downloads /AdvisoryCommittees /CommitteesMeetingMaterials/Drugs /CardiovascularandRenalDrugsAdvisoryCommittee /UCM421612.pdf. Accessed January 9, 2015. 9. Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med. 2011;364 (19):1788-1790.
6. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014;349:g4670. 7. An Idea for a Mid to Long Term Strategy for Pradaxa. Boehringer Ingelheim website.
JAMA March 10, 2015 Volume 313, Number 10 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/15/2015
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