- Email: [email protected]
Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran
Accepted Manuscript Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran Jeffrey Weitz, MD, Karen M. Earl, MSc, Kori Leblanc, PharmD, William Semchuk, MSc, PharmD, Fakhreddin Jamali, DPharm, PhD PII:
S0828-282X(18)30404-5
DOI:
10.1016/j.cjca.2018.05.023
Reference:
CJCA 2842
To appear in:
Canadian Journal of Cardiology
Received Date: 27 March 2018 Revised Date:
15 May 2018
Accepted Date: 22 May 2018
Please cite this article as: Weitz J, Earl KM, Leblanc K, Semchuk W, Jamali F, Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.05.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran Short Title: Generic formulations of dabigatran
Jeffrey I Weitz, MD, FACC, FCCS; Karen M Earl, MSc; Kori Leblanc, PharmD; William Semchuk,
RI PT
MSc, PharmD; Fakhreddin Jamali, DPharm, PhD
SC
Affiliations:
Karen M Earl, MSc, EBM Consulting, Inc.
M AN U
Jeffrey Weitz, MD, McMaster University and the Thrombosis and Atherosclerosis Research Institute
Kori Leblanc, PharmD, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto
TE D
William Semchuk, MSc, PharmD, Saskatchewan Health Authority and College of Pharmacy and Nutrition, College of Medicine, University of Saskatchewan
EP
Fakhreddin Jamali, DPharm, PhD, Professor of Pharmacy & Pharmaceutical Sciences, University of Alberta
AC C
Corresponding Author: Dr. Jeffrey Weitz Thrombosis and Atherosclerosis Research Institute 237 Barton St. E, Hamilton, Ontario, Canada L8L 2X2 Phone: (905) 574-8550 Email: [email protected]
Word Count of Manuscript: 1774
1
ACCEPTED MANUSCRIPT
Summary The science of assessing therapeutic equivalence must evolve to handle drugs such as
RI PT
dabigatran, for which two generic formulations have recently been approved in Canada. Branded dabigatran is formulated to maintain bioavailability with food and concomitant proton pump inhibitor (PPI) intake. Because testing with or without food or PPIs was not mandated for the generic
SC
dabigatran formulations, they may not be as safe and effective as the branded product. Abstract
M AN U
Dabigatran is widely used for stroke prevention in atrial fibrillation. Dabigatran is no longer patent protected in Canada and 2 generic formulations were recently approved by Health Canada. Branded dabigatran utilizes a complex formulation to maintain the acidic microenvironment required for maximal absorption. Consequently, food does not influence its bioavailability and the
TE D
efficacy and safety of dabigatran are similar with or without concomitant intake of proton pump inhibitors (PPIs). Unfortunately, current bioequivalence criteria do not mandate testing of the generic formulations with food or with concomitant intake of PPIs; thus the only data available for
EP
the approved generic products are in fasted, healthy volunteers. Without confirmation that the bioavailability of the generic dabigatran products is maintained in the presence of food or with co-
AC C
administration of PPIs, it is uncertain whether they will afford patients the same protection from stroke as the branded product. Clinicians and patients must be made aware of this limitation in order to make informed prescribing decisions. The rules for establishing bioequivalence have not kept pace with the increasing complexity of pharmaceutical products; we urge regulators to update the regulatory process to ensure the therapeutic equivalence of generic products. Introduction
2
ACCEPTED MANUSCRIPT Dabigatran is an oral thrombin inhibitor licensed in Canada for stroke prevention in atrial fibrillation. In addition to the branded product, two subsequent entry products (generics) were recently approved by Health Canada. Dabigatran is administered as a prodrug, dabigatran etexilate (DE), which has reduced bioavailability when the gastric pH is increased by food or drugs such as
RI PT
proton pump inhibitors. Branded DE utilizes a complex formulation to maintain the acidic
microenvironment required for maximal absorption. The bioequivalence criteria applied to the generic products do not require their evaluation in the setting of increased gastric pH, leaving
SC
uncertainty as to how these agents will perform in this common scenario. The purpose of this paper is to outline the current regulatory process for generics, describe particular challenges with
potential concerns about patient safety.
M AN U
dabigatran, and to highlight why the available data for the generic dabigatran formulations raise
Regulatory Process for Approval of Generics
The science of bioequivalence as a surrogate for therapeutic equivalence has served the
TE D
public well since the 1960s. The initial principles continue to be successfully applied for evaluation of the safety and efficacy of generics with straightforward release and stability characteristics. The rules are based on the concept that there is no difference between identical molecules that reach
EP
the systemic circulation in equal amounts regardless of the commercial source of the product. Nonetheless, like must be compared with like; thus, a capsule needs to be compared with a
AC C
capsule and not with a tablet or a patch. In routine bioequivalence testing, a cross-over design is used to compare drug levels between the generic and the brand in a small group of healthy volunteers. Studies are typically performed under fasted conditions and testing with food is not mandated. After administration of each product, serial blood samples are taken and the area under plasma concentration-time curve and the peak concentrations are recorded for comparison. The two products are considered
3
ACCEPTED MANUSCRIPT bioequivalent if the concentration parameters fall within 80 - 125% of each other within the 95% confidence interval. Dabigatran: A Complex Formulation The branded DE product (PRADAXA® Boehringer Ingelheim) is a complex formulation.
RI PT
Dabigatran, the active drug, is not orally bioavailable because of its high polarity. The etexilate salt is less polar and thus able to permeate the gut wall, but its limited solubility yields a bioavailability of only 5-7%. This solubility is pH-dependent; DE is soluble in an acidic environment and practically
SC
insoluble under alkaline conditions. Consequently, the bioavailability of DE varies as the gut pH ranges from acidic to alkaline due to intake of food or agents that increase gut pH such as proton
M AN U
pump inhibitors (PPIs).
To overcome the pH-dependency of DE bioavailability, branded DE capsules are filled with drug pellets each consisting of a tartaric acid core that is coated with a drug layer (Figure 1).1 Upon oral administration, the capsule releases its active ingredient along with the tartaric acid in the core.
TE D
The acidic core travels with the DE throughout the gut to maintain the acidic microenvironment that is necessary for absorption of the drug salt. Once absorbed, DE is rapidly and completely converted to dabigatran by non-specific esterases.
EP
This formulation endows PRADAXA with the optimal microenvironment to maximize bioavailability. The bioavailability of PRADAXA is not influenced by food and drug-drug interaction
AC C
studies indicate that concomitant administration with PPIs reduces bioavailability by less than 30%.2 The minimal impact of PPIs on the bioavailability of PRADAXA was confirmed in the RE-LY trial, which demonstrated similar outcomes in those taking or not taking PPIs.3 The two generic formulations of dabigatran approved in Canada are TEVA-DABIGATRAN® (Teva Canada Ltd.) and APO-DABIGATRAN® (Apotex Inc.). In accordance with routine bioequivalency criteria, these agents were tested in 48 and 110 healthy male and female subjects, respectively.4,5 For each, testing was limited to the 150 mg dose under fasting conditions. Both 4
ACCEPTED MANUSCRIPT generics are supplied in capsule format; TEVA-DABIGATRAN capsules contain tartaric acid pellets, whereas APO-DABIGATRAN capsules do not.5 Neither agent reports bioequivalence testing with co-administration of food or PPIs.
RI PT
Application of Bioequivalence Criteria to Complex Pharmaceuticals Pharmaceuticals are becoming increasingly complex. In addition to PRADAXA, other examples of complex pharmaceuticals include controlled-release formulations that incorporate
SC
conditioning and/or release modifying factors, agents with extended half-lives, and large molecules such as biologics. Routine bioequivalence criteria, developed decades prior to the introduction of
M AN U
these agents, are increasingly proving to be unsuitable surrogates for therapeutic equivalence with these complex drugs.
Standard bioequivalence criteria do not require testing in both fasting and fed conditions nor do they mandate time-based assessments that ensure that the bioequivalence evaluation is
TE D
appropriate for the half-life of the drug. For example, bioequivalence evaluation of generic forms of amiodarone were only performed in the fasted state despite the fact that its absorption is affected by food. Furthermore, amiodarone concentrations remained distinguishable from zero beyond 48
EP
hours after dosing because of the drug’s 55-day half-life. This finding rendered it impossible to accurately estimate the area under the curve to infinity. These limitations may explain the failures
AC C
reported with inter-generic switching.6
The experience with Methylphenidate, a drug used to control attention-deficit hyperactivity disorder, provides another example. The innovator product, Concerta® (Janssen), utilizes a multiphasic extended release pattern to preclude the development of acute tolerance, an issue that was observed with conventional extended release formulations.7 Nevertheless, generic extended release formulations received approval because regulatory rules did not consider release patterns when assigning therapeutic equivalence. A subsequent review revealed substantial treatment 5
ACCEPTED MANUSCRIPT failures in users of the generic foms.8 Consequently, the United States FDA reversed its decision, declaring that the generic products were not bioequivalent to Concerta and introducing revised bioequivalence standards to address the complex nature of multi-phasic products.9 A decision from Health Canada on this matter has yet to be provided.
RI PT
Implications for Patients
Because generic products are not required to undergo testing in any conditions beyond healthy, fasting volunteers, we have no confirmation that the bioavailability of the generic
SC
dabigatran products will be maintained in the presence of food or co-administration with PPIs. This is an important limitation because many users of dabigatran take their medication with food to
M AN U
minimize the risk of dyspepsia and with PPIs to reduce the potential for gastrointestinal bleeding.10 Changes in the bioavailability of dabigatran may be clinically important; it has been shown that clinical outcomes with dabigatran are dependent on trough plasma drug concentrations.3 Thus, there are drug concentrations below which the efficacy of the drug to prevent stroke is reduced and
TE D
above which the bleeding potential is increased.
Until the generic formulations demonstrate bioequivalence to the reference produce in the setting of increased gastric pH, we have no assurance that they afford a similar safety and efficacy
EP
profile as the brand drug. Therapeutic failure in the case of dabigatran is an increased incidence of stroke – a potentially fatal or permanently disabling event for patients. In addition to the profound
AC C
impact on patients, stroke represents a substantial expense to our health care system. The average estimated cost of ischemic stroke in Canada is $2.8 billion.11 Conclusions
In conclusion, clinicians and patients must be made aware of this limitation of generic
formulations of dabigatran so that they can make informed prescribing decisions. From a broader perspective, we must recognize that this issue will recur with increasing frequency as pharmaceutical formulations continue to increase in complexity. Society must have confidence that 6
ACCEPTED MANUSCRIPT approved generic drugs are as safe and effective as their brand-name counterparts. The science behind therapeutic equivalence is not keeping pace with the evolving science of pharmaceutics. To protect patients, we must correct this weakness in our regulatory process by developing and implementing new regulations that will ensure therapeutic equivalence of generic products as they
RI PT
come to market.
SC
Funding Sources: Boehringer Ingelheim Canada Ltd. provided an unrestricted grant to sponsor a half-day meeting attended by the authors to discuss the bioavailability profile of
M AN U
dabigatran and the associated clinical implications. Independently, the authors made the decision to produce this manuscript. Boehringer Ingelheim was not represented at the initial or any subsequent meetings or teleconferences, nor did they provide input into the writing or editing of the
TE D
manuscript.
Disclosures: Dr. Weitz has received consultant honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Novartis, Portola, and
EP
Pfizer. Ms. Earl has received fees for providing accredited continuing medical education programs sponsored by Amgen, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb,
AC C
Lilly, Novartis, Pfizer, sanofi, Servier; received consulting fees from Boehringer Ingelheim. Dr. Leblanc has received speaker/consultant honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Sanofi-Aventis; participated in research funded by Boehringer Ingelheim. Dr. Semchuk has received speaker/consultant honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Sanofi-Aventis and Servier; participated in research funded by AstraZeneca, Bristol Myers Squibb, Pfizer and Bayer. Dr. Jamali has served as consultant for many pharmaceutical houses including Boehringer Ingelheim of Canada. 7
ACCEPTED MANUSCRIPT
References 1. Adapted from United States Patent Application Publication. Wagner KG, Boeck G, Radtke
RI PT
G. July 18, 2013. Pub. No.: US 2013/0183384 A1. Available at http://pdfaiw.uspto.gov/.aiw?docid=20130183384&SectionNum=1&IDKey=8DDB8F7896A1& HomeUrl=http://appft.uspto.gov/netacgi/nph-
SC
Parser?Sect1=PTO2%2526Sect2=HITOFF%2526p=1%2526u=%25252Fnetahtml%25252F PTO%25252Fsearch-
M AN U
bool.html%2526r=1%2526f=G%2526l=50%2526co1=AND%2526d=PG01%2526s1=201301 83384.PGNR.%2526OS=DN/20130183384%2526RS=DN/20130183384. Accessed on April 19, 2018.
2. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy
TE D
volunteers and patients undergoing total hip replacement. Stangier J, Eriksson BI, Dahl OE et al. J Clin Pharmacol 2005 May;45(5):555-63. 3. The effect of dabigatran plasma concentrations and patient characteristics on the frequency
EP
of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). Reilly PA, Lehr T, Haertter
AC C
S et al. J Am Coll Cardiol 2014 Feb 4;63(4):321-8. 4. TEVA-DABIGATRAN Product Monograph. Teva Canada Limited. April 26, 2017. Available at https://pdf.hres.ca/dpd_pm/00043966.PDF. Accessed on April 19, 2018. 5. APO-DABIGATRAN Product Monograph. Apotex Inc. Oct. 10, 2017. Available at https://pdf.hres.ca/dpd_pm/00043971.PDF. Accessed on April 19, 2018.
8
ACCEPTED MANUSCRIPT 6. Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias. Reiffel JA, Kowey PR. Am J Cardiol. 2000 May 1;85(9):1151-3, A10. 7. Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate
2012 Dec;14(4):925-6.
RI PT
Multiphasic Modified Release Formulations. Stier EM, Davit BM, Chandaroy P et al. AAPS J
8. U.S. Food and Drug Administration. Questions and Answers Regarding Methylphenidate Hydrochloride Extended Release Tablets (generic Concerta) made by Mallinckrodt and
SC
UCB/Kremers Urban (formerly Kudco). Available at
M AN U
https://www.fda.gov/Drugs/DrugSafety/ucm422569.htm. Accessed on March 15, 2018. 9. U.S. Food and Drug Administration. Bioequivalence Recommendations for CONCERTA (Methylphenidate Hydrochloride) Extended-Release Tablets; Draft Guidance for Industry; Availability. Available at https://www.federalregister.gov/documents/2014/11/06/2014-
extended-release-
TE D
26306/bioequivalence-recommendations-for-concerta-methylphenidate-hydrochloride-
tablets?utm_campaign=pi+subscription+mailing+list&utm_medium=email&utm_source=fede
EP
ralregister.gov. Accessed on March 15, 2018. 10. Risk of gastrointestinal adverse effects of dabigatran compared with warfarin among
AC C
patients with atrial fibrillation: a nationwide cohort study. Staerk L, Gislason GH, Lip GY et al. Europace 2015 Aug;17(8):1215-22. 11. Impact of Disability Status on Ischemic Stroke Costs in Canada in the First Year. Mittmann N, Seung SJ, Hill MD et al. Can J Neurol Sci 2012 Nov;39(6):793-800.
9
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Figures
AC C
EP
TE D
Figure 1: Structure of branded dabigatran etexilate pellets
1
S0828-282X(18)30404-5
DOI:
10.1016/j.cjca.2018.05.023
Reference:
CJCA 2842
To appear in:
Canadian Journal of Cardiology
Received Date: 27 March 2018 Revised Date:
15 May 2018
Accepted Date: 22 May 2018
Please cite this article as: Weitz J, Earl KM, Leblanc K, Semchuk W, Jamali F, Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.05.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran Short Title: Generic formulations of dabigatran
Jeffrey I Weitz, MD, FACC, FCCS; Karen M Earl, MSc; Kori Leblanc, PharmD; William Semchuk,
RI PT
MSc, PharmD; Fakhreddin Jamali, DPharm, PhD
SC
Affiliations:
Karen M Earl, MSc, EBM Consulting, Inc.
M AN U
Jeffrey Weitz, MD, McMaster University and the Thrombosis and Atherosclerosis Research Institute
Kori Leblanc, PharmD, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto
TE D
William Semchuk, MSc, PharmD, Saskatchewan Health Authority and College of Pharmacy and Nutrition, College of Medicine, University of Saskatchewan
EP
Fakhreddin Jamali, DPharm, PhD, Professor of Pharmacy & Pharmaceutical Sciences, University of Alberta
AC C
Corresponding Author: Dr. Jeffrey Weitz Thrombosis and Atherosclerosis Research Institute 237 Barton St. E, Hamilton, Ontario, Canada L8L 2X2 Phone: (905) 574-8550 Email: [email protected]
Word Count of Manuscript: 1774
1
ACCEPTED MANUSCRIPT
Summary The science of assessing therapeutic equivalence must evolve to handle drugs such as
RI PT
dabigatran, for which two generic formulations have recently been approved in Canada. Branded dabigatran is formulated to maintain bioavailability with food and concomitant proton pump inhibitor (PPI) intake. Because testing with or without food or PPIs was not mandated for the generic
SC
dabigatran formulations, they may not be as safe and effective as the branded product. Abstract
M AN U
Dabigatran is widely used for stroke prevention in atrial fibrillation. Dabigatran is no longer patent protected in Canada and 2 generic formulations were recently approved by Health Canada. Branded dabigatran utilizes a complex formulation to maintain the acidic microenvironment required for maximal absorption. Consequently, food does not influence its bioavailability and the
TE D
efficacy and safety of dabigatran are similar with or without concomitant intake of proton pump inhibitors (PPIs). Unfortunately, current bioequivalence criteria do not mandate testing of the generic formulations with food or with concomitant intake of PPIs; thus the only data available for
EP
the approved generic products are in fasted, healthy volunteers. Without confirmation that the bioavailability of the generic dabigatran products is maintained in the presence of food or with co-
AC C
administration of PPIs, it is uncertain whether they will afford patients the same protection from stroke as the branded product. Clinicians and patients must be made aware of this limitation in order to make informed prescribing decisions. The rules for establishing bioequivalence have not kept pace with the increasing complexity of pharmaceutical products; we urge regulators to update the regulatory process to ensure the therapeutic equivalence of generic products. Introduction
2
ACCEPTED MANUSCRIPT Dabigatran is an oral thrombin inhibitor licensed in Canada for stroke prevention in atrial fibrillation. In addition to the branded product, two subsequent entry products (generics) were recently approved by Health Canada. Dabigatran is administered as a prodrug, dabigatran etexilate (DE), which has reduced bioavailability when the gastric pH is increased by food or drugs such as
RI PT
proton pump inhibitors. Branded DE utilizes a complex formulation to maintain the acidic
microenvironment required for maximal absorption. The bioequivalence criteria applied to the generic products do not require their evaluation in the setting of increased gastric pH, leaving
SC
uncertainty as to how these agents will perform in this common scenario. The purpose of this paper is to outline the current regulatory process for generics, describe particular challenges with
potential concerns about patient safety.
M AN U
dabigatran, and to highlight why the available data for the generic dabigatran formulations raise
Regulatory Process for Approval of Generics
The science of bioequivalence as a surrogate for therapeutic equivalence has served the
TE D
public well since the 1960s. The initial principles continue to be successfully applied for evaluation of the safety and efficacy of generics with straightforward release and stability characteristics. The rules are based on the concept that there is no difference between identical molecules that reach
EP
the systemic circulation in equal amounts regardless of the commercial source of the product. Nonetheless, like must be compared with like; thus, a capsule needs to be compared with a
AC C
capsule and not with a tablet or a patch. In routine bioequivalence testing, a cross-over design is used to compare drug levels between the generic and the brand in a small group of healthy volunteers. Studies are typically performed under fasted conditions and testing with food is not mandated. After administration of each product, serial blood samples are taken and the area under plasma concentration-time curve and the peak concentrations are recorded for comparison. The two products are considered
3
ACCEPTED MANUSCRIPT bioequivalent if the concentration parameters fall within 80 - 125% of each other within the 95% confidence interval. Dabigatran: A Complex Formulation The branded DE product (PRADAXA® Boehringer Ingelheim) is a complex formulation.
RI PT
Dabigatran, the active drug, is not orally bioavailable because of its high polarity. The etexilate salt is less polar and thus able to permeate the gut wall, but its limited solubility yields a bioavailability of only 5-7%. This solubility is pH-dependent; DE is soluble in an acidic environment and practically
SC
insoluble under alkaline conditions. Consequently, the bioavailability of DE varies as the gut pH ranges from acidic to alkaline due to intake of food or agents that increase gut pH such as proton
M AN U
pump inhibitors (PPIs).
To overcome the pH-dependency of DE bioavailability, branded DE capsules are filled with drug pellets each consisting of a tartaric acid core that is coated with a drug layer (Figure 1).1 Upon oral administration, the capsule releases its active ingredient along with the tartaric acid in the core.
TE D
The acidic core travels with the DE throughout the gut to maintain the acidic microenvironment that is necessary for absorption of the drug salt. Once absorbed, DE is rapidly and completely converted to dabigatran by non-specific esterases.
EP
This formulation endows PRADAXA with the optimal microenvironment to maximize bioavailability. The bioavailability of PRADAXA is not influenced by food and drug-drug interaction
AC C
studies indicate that concomitant administration with PPIs reduces bioavailability by less than 30%.2 The minimal impact of PPIs on the bioavailability of PRADAXA was confirmed in the RE-LY trial, which demonstrated similar outcomes in those taking or not taking PPIs.3 The two generic formulations of dabigatran approved in Canada are TEVA-DABIGATRAN® (Teva Canada Ltd.) and APO-DABIGATRAN® (Apotex Inc.). In accordance with routine bioequivalency criteria, these agents were tested in 48 and 110 healthy male and female subjects, respectively.4,5 For each, testing was limited to the 150 mg dose under fasting conditions. Both 4
ACCEPTED MANUSCRIPT generics are supplied in capsule format; TEVA-DABIGATRAN capsules contain tartaric acid pellets, whereas APO-DABIGATRAN capsules do not.5 Neither agent reports bioequivalence testing with co-administration of food or PPIs.
RI PT
Application of Bioequivalence Criteria to Complex Pharmaceuticals Pharmaceuticals are becoming increasingly complex. In addition to PRADAXA, other examples of complex pharmaceuticals include controlled-release formulations that incorporate
SC
conditioning and/or release modifying factors, agents with extended half-lives, and large molecules such as biologics. Routine bioequivalence criteria, developed decades prior to the introduction of
M AN U
these agents, are increasingly proving to be unsuitable surrogates for therapeutic equivalence with these complex drugs.
Standard bioequivalence criteria do not require testing in both fasting and fed conditions nor do they mandate time-based assessments that ensure that the bioequivalence evaluation is
TE D
appropriate for the half-life of the drug. For example, bioequivalence evaluation of generic forms of amiodarone were only performed in the fasted state despite the fact that its absorption is affected by food. Furthermore, amiodarone concentrations remained distinguishable from zero beyond 48
EP
hours after dosing because of the drug’s 55-day half-life. This finding rendered it impossible to accurately estimate the area under the curve to infinity. These limitations may explain the failures
AC C
reported with inter-generic switching.6
The experience with Methylphenidate, a drug used to control attention-deficit hyperactivity disorder, provides another example. The innovator product, Concerta® (Janssen), utilizes a multiphasic extended release pattern to preclude the development of acute tolerance, an issue that was observed with conventional extended release formulations.7 Nevertheless, generic extended release formulations received approval because regulatory rules did not consider release patterns when assigning therapeutic equivalence. A subsequent review revealed substantial treatment 5
ACCEPTED MANUSCRIPT failures in users of the generic foms.8 Consequently, the United States FDA reversed its decision, declaring that the generic products were not bioequivalent to Concerta and introducing revised bioequivalence standards to address the complex nature of multi-phasic products.9 A decision from Health Canada on this matter has yet to be provided.
RI PT
Implications for Patients
Because generic products are not required to undergo testing in any conditions beyond healthy, fasting volunteers, we have no confirmation that the bioavailability of the generic
SC
dabigatran products will be maintained in the presence of food or co-administration with PPIs. This is an important limitation because many users of dabigatran take their medication with food to
M AN U
minimize the risk of dyspepsia and with PPIs to reduce the potential for gastrointestinal bleeding.10 Changes in the bioavailability of dabigatran may be clinically important; it has been shown that clinical outcomes with dabigatran are dependent on trough plasma drug concentrations.3 Thus, there are drug concentrations below which the efficacy of the drug to prevent stroke is reduced and
TE D
above which the bleeding potential is increased.
Until the generic formulations demonstrate bioequivalence to the reference produce in the setting of increased gastric pH, we have no assurance that they afford a similar safety and efficacy
EP
profile as the brand drug. Therapeutic failure in the case of dabigatran is an increased incidence of stroke – a potentially fatal or permanently disabling event for patients. In addition to the profound
AC C
impact on patients, stroke represents a substantial expense to our health care system. The average estimated cost of ischemic stroke in Canada is $2.8 billion.11 Conclusions
In conclusion, clinicians and patients must be made aware of this limitation of generic
formulations of dabigatran so that they can make informed prescribing decisions. From a broader perspective, we must recognize that this issue will recur with increasing frequency as pharmaceutical formulations continue to increase in complexity. Society must have confidence that 6
ACCEPTED MANUSCRIPT approved generic drugs are as safe and effective as their brand-name counterparts. The science behind therapeutic equivalence is not keeping pace with the evolving science of pharmaceutics. To protect patients, we must correct this weakness in our regulatory process by developing and implementing new regulations that will ensure therapeutic equivalence of generic products as they
RI PT
come to market.
SC
Funding Sources: Boehringer Ingelheim Canada Ltd. provided an unrestricted grant to sponsor a half-day meeting attended by the authors to discuss the bioavailability profile of
M AN U
dabigatran and the associated clinical implications. Independently, the authors made the decision to produce this manuscript. Boehringer Ingelheim was not represented at the initial or any subsequent meetings or teleconferences, nor did they provide input into the writing or editing of the
TE D
manuscript.
Disclosures: Dr. Weitz has received consultant honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Novartis, Portola, and
EP
Pfizer. Ms. Earl has received fees for providing accredited continuing medical education programs sponsored by Amgen, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb,
AC C
Lilly, Novartis, Pfizer, sanofi, Servier; received consulting fees from Boehringer Ingelheim. Dr. Leblanc has received speaker/consultant honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Sanofi-Aventis; participated in research funded by Boehringer Ingelheim. Dr. Semchuk has received speaker/consultant honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Sanofi-Aventis and Servier; participated in research funded by AstraZeneca, Bristol Myers Squibb, Pfizer and Bayer. Dr. Jamali has served as consultant for many pharmaceutical houses including Boehringer Ingelheim of Canada. 7
ACCEPTED MANUSCRIPT
References 1. Adapted from United States Patent Application Publication. Wagner KG, Boeck G, Radtke
RI PT
G. July 18, 2013. Pub. No.: US 2013/0183384 A1. Available at http://pdfaiw.uspto.gov/.aiw?docid=20130183384&SectionNum=1&IDKey=8DDB8F7896A1& HomeUrl=http://appft.uspto.gov/netacgi/nph-
SC
Parser?Sect1=PTO2%2526Sect2=HITOFF%2526p=1%2526u=%25252Fnetahtml%25252F PTO%25252Fsearch-
M AN U
bool.html%2526r=1%2526f=G%2526l=50%2526co1=AND%2526d=PG01%2526s1=201301 83384.PGNR.%2526OS=DN/20130183384%2526RS=DN/20130183384. Accessed on April 19, 2018.
2. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy
TE D
volunteers and patients undergoing total hip replacement. Stangier J, Eriksson BI, Dahl OE et al. J Clin Pharmacol 2005 May;45(5):555-63. 3. The effect of dabigatran plasma concentrations and patient characteristics on the frequency
EP
of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). Reilly PA, Lehr T, Haertter
AC C
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ACCEPTED MANUSCRIPT 6. Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias. Reiffel JA, Kowey PR. Am J Cardiol. 2000 May 1;85(9):1151-3, A10. 7. Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate
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patients with atrial fibrillation: a nationwide cohort study. Staerk L, Gislason GH, Lip GY et al. Europace 2015 Aug;17(8):1215-22. 11. Impact of Disability Status on Ischemic Stroke Costs in Canada in the First Year. Mittmann N, Seung SJ, Hill MD et al. Can J Neurol Sci 2012 Nov;39(6):793-800.
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Figures
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Figure 1: Structure of branded dabigatran etexilate pellets
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