Scientific And Regulatory Background For The Revised Bioequivalence Requirements For NTI, Steep Exposure-Response, And Drugs With Complex PK Profiles Liang Zhao, Ph.D. Director, Division of Quantitative Methods and Modeling Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research, FDA AAPS, Denver November 13th, 2016
Outline of Presentation to Facilitate Discussion 1. NTI drug general characteristics and evaluation 2. Drug with steep exposure response relationship: the Dabigatran case 3. Drugs with complex PK profiles: the methylphenidate case 2 2
NTI Drugs Narrow therapeutic index (NTI) drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. LX Yu et. al. CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 00 NUMBER 00 MONTH 2014 3 3
Current Criteria for NTI Classification 1. There is little separation between therapeutic and toxic doses or the associated blood/plasma concentrations 2. Sub-therapeutic drug concentration may lead to serious therapeutic failure or adverse events 3. They are subject to therapeutic drug monitoring (TDM) based on pharmacokinetic (PK) or pharmacodynamics (PD) measures 4. They possess low-to-moderate (i.e., no more than 30%) within-subject variability 5. Doses are often adjusted in very small increments (less than 20%) 4
Revised BE Study Design and Criteria for NTI Drugs Recommended Study Design: 2-sequence, 4-way, fully replicated BE studies P1 P2 P3 P4 TRTR T1 R1 T2 R2 RTRT R1 T1 R2 T2 CV WR L - U 5 94.87-105.41 10 90.02-111.08 15 85.35-117.02 20 81.17-123.20 >21.42 80.00-125.00 5 5
RSABE to Compare Means Fully replicated TRTR/RTRT design RSABE model (μ T μ R ) 2 σ WR 2 θ, θ = ln( )2 2 σ W0 µ T & µ R : average of the log-transformed PK measure for the test and reference products σ WR : within-subject standard deviation for the reference product θ: scaled average BE limit = 1.11 Δ: upper BE limit, assigned as 1/0.9 σ W0 : regulatory constant, assigned to 0.1 6 6
New Approach to Compare Variability Comparison of σ WT with σ WR Mixed effects model of intra-subject contrast T1-T2 and R1-R2 by sequence Comparison based on s wt & s wr (the estimate of σ WT & σ WR ) One side F test: σ WT σ WR δ 90% CI for σ WT σ WR is given as below and BE if upper limit of the 90% CI 2.5 s wt /s wr, (v 1,v 2 ) Fα 2 s wt /s wr F α(v 1 1,v 2 ) 2 7 7
RSABE vs. Tightened ABE Limits Other 100 agencies use tightened ABE limits Passing Rate (%) 80 s WR = 0.05 AUC 90-111.11% 60 Cmax 90-111.11% or 80-125%, case 40by case e.g. 20EMA & Health Canada Tightened 0 ABE limits could be too 0.8 0.9 1 1.1 1.2 strict in some cases Geometric Mean Ratio RLD compared s to itself WR = 0.25 (GMR=1, 100 s WR = s WT ): passing rate = 91.18% 80 RLD 60compared to a generic (GMR=0.95, s WR = s WT ): passing rate 40 = 52% Passing Rate (%) 20 0 0.8 0.9 1 1.1 1.2 Geometric Mean Ratio Passing Rate (%) 100 80 60 40 20 s WR = 0.15 0 0.8 0.9 1 1.1 1.2 Geometric Mean Ratio Average BE 80-125% Average BE 90-111.111% Scaled BE Scaled BE + PEC 80-125% Scaled BE + PEC 90-111.111% Scaled BE + PEC 95-105.263% s WR = s WT 8 8
Drugs Using NTI Approach for BE Antiepileptic (AED) Carbamazepine Phenytoin Valproic acid Immunosuppressant Cyclosporine Everolimus Tacrolimus Sirolimus Anticoagulant Warfarin Others Digoxin Levothyroxine Valproic acid More to come 9
Drugs with Steep Exposure-Response: Case of Dabigatran 10
Non-Vitamin K antagonist oral anticoagulants (NOACs) Dabigatran (Pradaxa)- thrombin inhibitor Approved October 2010 Draft BE guidance posted (2012) Rivaroxaban (Xarelto)-factor Xa inhibitor Aproved November 2011 Apixaban (Eliquis)-factor Xa inhibitor Approved December 2012 Draft BE guidance posted (2013) Edoxaban (Savaysa)-factor Xa inhibitor Approved January 2015 Indication: reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. http://inside.fda.gov:9003/downloads/employeeresources/training/trainingcder/ucm432724.pdf 11 11
Dabigatran Exhibits Concentration Dependent Relationship on Ischemic Stroke & Life-Threatening Bleeds http://inside.fda.gov:9003/downloads/employeeresources/training/trainingcder/ucm429298.pdf 12 12
Direct & Reversible Thrombin Inhibition No Delay Between Exposure (Cmax) and Anticoagulant Effect (Emax) http://inside.fda.gov:9003/downloads/employeeresources/training/trainingcder/ucm429298.pdf 13 13
Dabigatran PK and E-R Properties Variable blood levels (renal function, weight, drug-drug interactions), a problem when C-R relationships are steep Steep Exposure Response relationship Serious consequences of being either too low or too high and you do not see them until they occur (no marker, nothing to titrate too, and quite delayed) (quote from Dr. Bob Temple) 14 14
Is Dabigatran a Narrow Therapeutic Index (NTI) Drug? 1. There is little separation between therapeutic and toxic doses or the associated blood/plasma concentrations (Appears yes) 2. Sub-therapeutic drug concentration may lead to serious therapeutic failure or adverse events (Appears yes) 3. They are subject to therapeutic drug monitoring based on pharmacokinetic (PK) or pharmacodynamics (PD) measures (No based on label) 4. They possess low-to-moderate (i.e., no more than 30%) within-subject variability (No, >40%) 5. Doses are often adjusted in very small increments (less than 20%) (No, only 150 and 75 mg strength available in US) 15 15
BE Recommendation before Revision http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm308030.pdf 16 16
BE Guidance post Revision NTI criteria in essence 17
Drugs with Complex PK Profiles 18
Methylphenidate ER Products Safety report for certain generics: lack of efficacy later at the day Certain generics (X) showed different PK profiles Failed pauc 7-12hr The clinical relevance is unknown Clinical trial simulation on PD profiles using the generic s PK profiles as input showed that the pauc is important for efficacy during this time window. PK/PD simulations can help regulatory decision making 19
Concerta and Generic X Tablet Design Concerta Drug overcoat : 22% of drug; IR portion Tablet core : 78% of drug; ER portion Push compartment : Osmotically active Difference Generic X Drug overcoat : 11.1% of drug; IR portion Tablet core : 88.9% of drug; ER portion Matrix ER core Slide Courtesy of Wenlei Jiang, Ph.D. 20 20
BE: Concerta vs Generic X different formulation design Fasting C max (90%CI: 80.98 88.78) and AUC 7-12 (90%CI: 64.14-72.42) 21 21
X/Concerta SKAMP pauec Ratio different formulation design Test/RLD Ratio pauec 0-3hr Median 0.970 5% CI 0.804 95% CI 1.265 pauec 3-7hr Median 0.967 5% CI 0.839 95% CI 1.076 pauec 7-12hr Median 0.829 5% CI 0.613 95% CI 0.979 22 22
Concerta Guidance Revision Initiated due to product complaints associated with the two approved generics Generic products failed pauc metrics tied to late afternoon efficacy A 4-way fully replicated crossover study at fasting and fed conditions are requested to demonstrate product BE Bioequivalence based on (90% CI): Fasting Study: AUC 0-3, AUC 3-7, AUC 7-12, AUC 0-, and C max, Fed study: AUC 0-4, AUC 4-8, AUC 8-12, AUC 0-, and C max, Pending ANDAs with similar design mechanism can pass Subject by formulation interaction: to be discussed 23 23
Summary NTI: RSABE approach and variance ratio test Drugs with Steep Exposure-Response Relationship: NTI like approach can be used Drugs With Complex PK Profiles: Partial AUC based on PK-PD relationship The final BE recommendation can be case specific and a collective approach based on the product formulation, PK and PK-PD characteristics 24
CDER\OGD\ORS Acknowledgements Robert Lionberger, Ph.D. Lanyan (Lucy) Fang, Ph.D. Xinyuan (Susie) Zhang, Ph.D. Andrew Babiskin, Ph.D. Other ORS contributors CDER\OGD\OB, CDER\OTS\OCP, CDER\OTS\OB 25