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Shiew-Mei Huang

Obstetric-Fetal Pharmacology Research Units (OPRU) Network Steering Committee Meeting March 29, 2011, Bethesda, MD

Applications of Pharmacogenomics in Drug Development & Regulatory Review - Recent relabeling of Drug Products Shiew-Mei Huang, Ph.D. Deputy Director Office of Clinical Pharmacology (OCP) OTS, CDER, FDA shiewmei.huang@fda.hhs.gov

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Factors Affecting Drug Exposure/Response

<Huang S-M, Temple R, Clin Pharmacol Ther 84: 287-294, 2008> <FDA Clinical Pharmacology guidance documents: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances 2 /ucm064982.htm>

Applications of pharmacogenomics in drug development and regulatory review- recent relabeling of drug products OPRU meeting, March 28, 2011, Bethesda, MD

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Shiew-Mei Huang

Comparative exposure and dose recommendation in subgroups with various patient factors

(Data compiled from labeling for Crestor (rosuvastatin; AstraZeneca);
Labeling from http://www.accessdata.fda.gov/scripts/cder/drugsatfda.); November 2007 labeling

ÆCurrent practice: Adjust the dose to achieve similar systemic exposure Æ Only the first step
<Huang S-M, Temple R, Clin Pharmacol Ther. 84(3): 287-294, 2008>
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Safety-Related Labeling Changes
(changes made Oct 2002-Aug 2005, n=2645 label changes for 1601 NDA/BLA entries) 220 200 180 160 140 120 100 80 60 40 20 0
0 5 10 15 20 25 30 35 40 45 50 55 60

rosuvastatin
Black Box Warnings

atorvastatin clopidogrel simvastatin

Warnings Precautions Contraindications Adverse Reactions

warfarin

codeine

Years post-approval

Modified from: T Mullin, CDER, Office of Planning and Analysis, OTS presentation, May 2009

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Applications of pharmacogenomics in drug development and regulatory review- recent relabeling of drug products OPRU meeting, March 28, 2011, Bethesda, MD

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2011. March 28. N Engl J Med 2008.Shiew-Mei Huang Labeling Example (1) Updating labeling Genetic DataÆ Drug Interaction warning 5 S-M Huang CYP2C19 and Clopidogrel Composite Clinical Outcome* Carriers Non-Carriers Active Metabolite AUC Carriers: with at least one variant alleles.10. PM: with two reduced function alleles *2. 5. IM: one reduced function allele *Outcome: a composite of death from EM: no variant alleles. myocardial infarction. MD 3 . http://content. 3.recent relabeling of drug products OPRU meeting. 8 (IM+PM). cardiovascular causes. 4.nejm. Bethesda. N Engl J Med 2008.1056/NEJMoa0809171 > <Simon T et al. UM: one or two *17 or stroke <Mega J et al.org/cgi/content/full/360/4/363> Another study also examined MDR1 6 S-M Huang Applications of pharmacogenomics in drug development and regulatory review.

Shiew-Mei Huang WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS • Effectiveness of Plavix depends on activation … by ….COGENT trial|October 6. 2011..g.L.recent relabeling of drug products OPRU meeting. Bethesda.“HIGHLIGHTS”) http://www.accessdata. Bhatt et al.1056/NEJMoa1007964) 8 S-M Huang Huang Applications of pharmacogenomics in drug development and regulatory review.pdf http://www. CYP2C19 • Poor metabolizers …. CYP2C19 genotype … • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers WARNINGS AND PRECAUTIONS • Avoid concomitant use with drugs that inhibit CYP2C19 (e.accessdata. omeprazole) Drugs at the FDA (Plavix. but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. March 28. or … percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function • Tests are available to identify .fda. D..gov/drugsatfda_docs/label/2010/020839s042lbl. prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. 2010|(DOI: 10.gov/Scripts/cder/DrugsatFDA/ 7 S-M Huang Huang March 2010 Relabeling October 2010 Publication Æ Among patients receiving aspirin and clopidogrel. There was no apparent cardiovascular interaction between clopidogrel and omeprazole.fda.. exhibit higher cardiovascular event rates following … acute coronary syndrome (ACS). MD 4 .

University of Virginia pharmacotherapy newsletter: Pediatric Pharmacotherapy.pdf • Median Starting dose is 1.Shiew-Mei Huang Clopidogrel and Pharmacogenetic Test in Clinical Practice (one example) • Vanderbilt University Medical Center joins Scripps Clinic. 17 (gain-of-function) • Individual clinicians to decide treatment options .edu/alive/pediatrics/PharmNews/2 01005.Buck ML.2-8.virginia. Pediatr Cardiol 2009.If Æ . 2011.If Æ homozygous for loss-of-function prasugrel contraindications for prasugrel increase the dose from 75 to 150 mg or ticagrelor when it is available 9 S-M Huang http://www.FDA review . 2.recent relabeling of drug products OPRU meeting. 2010) Clopidogrel Use in Pediatrics • “Current Studies suggest that a dose of 0. Bethesda.theheart. 30:99-105 • No pharmacogenetic information in pediatrics • “The clopidogrel dose (0.9 me/kg/day) --Children’s Hospital in Boston .Krudys K et al. http://www.Maltz LA.do (October 21.gov/downloads/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/UCM242999.3 mg/kg/day (0. May 2010.org/article/1139495. starting to routinely test for variations in CYP2C19 gene before antiplatelet therapy • Test for *1 (wild). July 2010.fda. 3 (loss-of-function). Clinical Pharmacology Review.pdf 10 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. http://www.2 mg/kg) used in the pivotal CLARINET study was potentially inadequate to demonstrate efficacy”-. March 28.healthsystem.2 to 1 mg/kg/day may be an appropriate starting point” . et al. MD 5 .

Shiew-Mei Huang Clinical Utility December 2010 11 S-M Huang Clinical Utility (2) Cisplatin & ototoxicity Lesko. March 28. LJ & Huang S-M. MD 6 . 2011. Clin Pharmacol Ther 89(4): 489-490 (April 2011) April 2011 12 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. Bethesda.recent relabeling of drug products OPRU meeting.

2011. March 28. MD 7 .Shiew-Mei Huang Clinical Utility (2) Cisplatin & ototoxicity Lesko. LJ & Huang S-M. Bethesda.recent relabeling of drug products OPRU meeting. Clin Pharmacol Ther 89(4): 489-490 (April 2011) April 2011 13 S-M Huang Labeling Example (2) Warfarin 14 S-M Huang Applications of pharmacogenomics in drug development and regulatory review.

Gender. VKORC1) Wadelius et al. Caldwell et al. Clin Med Res 2007 15 S-M Huang Frequency of VKORC1 -1639 G>A Caucasians (N=297) Spanish (N=105) Chinese (N=104) African Americans (N=159) AA 19% 32% 80% 0% AG 56% 40% 18% 21% GG 25% 28% 2% 79% Asians may need a lower dose <Sconce et al. Human Mol Genetics 2005. Gage et al. Montes et al Br J Haemat 2006> 16 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. 2011. March 28. Bethesda. MD 8 . Race. Yuan et al. Schelleman et al. Drugs. Blood 2005. Clin Pharmacol Ther 2008.recent relabeling of drug products OPRU meeting.Shiew-Mei Huang Predicting the Warfarin Stable Dose Age. BW. Clin Pharmacol Ther 2007. Blood 2009. Diet Others Genotypes (CYP2C9.

Huang.5-2 mg . Linder.5-2 mg .“Initial Dosage”) http://www. 2011. Bethesda.aspx 17 S-M Huang January 2010 Relabeling VKORC1 *1*1 GG AG AA 5-7 mg 5-7 mg 3-4 mg *1*2 5-7 mg 3-4 mg 3-4 mg CYP2C9 *1*3 *2*2 3-4 mg 3-4 mg 3-4 mg 3-4 mg *2*3 3-4 mg *3*3 . Jaffer. Clin Pharmacol & Ther.aacc.5-2 mg .Shiew-Mei Huang Public Debates LJ Lesko.gov/drugsatfda_docs/label/2010/009218s108lbl. Clin Pharmacol & Ther.5-2 mg .5-2 mg .5-2 mg . MD 9 .pdf http://www. March 28.accessdata. July 28.recent relabeling of drug products OPRU meeting.fda.5-2 mg Drugs at the FDA (COUMADIN. September 2008 DA Garcia.accessdata.org/publications/cln/2008/July/dailies/Pages/mon_daily1. September 2008 AACC warfarin Debate: Hallworth.fda. Eby.gov/Scripts/cder/DrugsatFDA/ 18 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. 2008 http://www.

g.50 1. WI. 2011 19 S-M Huang Genotype.40 0.60 0.50 2.20 1. ___ EM Control ___ PM Control Mean Values of Systemic Concentration in Plasma of Sulfaphenazole over Time 2. Age 20-40 yr 7-OH Warfarin CL’int (uL/min/pmol CYP) EM (*1/*1) 0.50 0.00 1. atmoxetine lableing) Applications of pharmacogenomics in drug development and regulatory review. TN. Lesko.00 0 24 48 72 96 120 Time . _ _ _ PM +Inh.1 PMI/ PM=1.20 0.8 EMI/EM=1. Bethesda.00 0.8 PM/EM=3. Memphis.1 PM/EM=3.034 PM (*3/*3) 0.recent relabeling of drug products OPRU meeting.00 Systemic Concentration (mg/L) PMI/PM=1.Inhibitor (h) Mean Systemic Concentration in Plasma of SWarfarin with and without Interaction over Time 1. March 19.0. L. March 28. Pop 2: CYP2C9 PM.Shiew-Mei Huang Warfarin Use in Pediatrics • Warfarin Pharmacogenomics in Pediatric Patients – Pilot Project Critical Path Initiative Collaborators Greg Kearns – Kansas City Ron Hines – Milwaukee Cheryl Takao – Los Angeles • PG in Pediatric Heart Transplantation (Un.20 ___ EM Control ___ PM Control _ _ _ EM +Inh.. 2011.005 Using SimCYP® V8. M/F=1. Merrimac. September 2009> Æ Which population needs dose adjustment? 20 S-M Huang (e. presentation at PPAG (Pediatric Pharmacy Advocacy Group) . MD Systemic Concentration (mg/L) 10 . Zhang L.00 0. of Pittsburgh) Burckart G.Specific Inhibition Effect S-warfarin: SD 10 mg on day 1 Sulfaphenazole: QD 2000 mg 5 days Pop 1: CYP2C9 EM.9 Substrate 0 24 48 72 96 120 Time . LOL presentation. Huang S-M.80 0.Substrate (h) Inhibitor <Zhao P.

March 28. Gil Berglund E. Brar SS. Bethesda. Booth BP. Grillo JA. 2011. Intrinsic/extrinsic Factors B.Shiew-Mei Huang Application of Physiologically-based Pharmacokinetic (PBPK) Modeling A. Lesko LJ. Zhang L. 21 S-M Huang Huang S-M. Moon YJ. Liu Q. 2011)> Predict. Confirm Labeling Example (3) Statins & Transporters 22 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. PBPK Model components System component (drug-independent) Lung Rapidly perfused organs Slowly perfused organs Drug-dependent component ADME. Madabushi R. 2008 Individual or combined effects on human physiology Intestines Dosing Elimination PBPK Model <Zhao P. PK. Reynolds KS. 89:259-267 (February. Clin Pharmacol Ther. Wu TC. Learn. Rahman NA. MD 11 .recent relabeling of drug products OPRU meeting. Bullock JM. PD and MOA Kidney Liver Metabolism Active transport Passive diffusion Protein binding Drug-drug interactions Receptor binding Blood Blood Huang and Temple. Song P.

Huang S-M. Toxicology Mechanisms and Methods. Legato M.. Huang S-M. S-M. Ed. Nature Reviews Drug Discovery. 2004. 2010 24 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. “Principles of Gender-Specific Medicine”. Giacomini KM. Zhang L. et al. 2006 * remarketed with restricted distribution ** Technetium (99m Tc) fanolesomab Human Transport Proteins 1. Drug-drug interactions Acute liver failure Rhabdomyolysis. International Transporter Consortium. Nature Reviews Drug Discovery. 2011. stroke CYP/transporter substrate Skin reactions (SJS) Brain infection Cardiopulmonary arrest Liver failure Fatal arrhythmia Risk High blood pressure/Chronic stable angina NSAID Antihistamine Antihistamine Grepafloxacin Antibiotics Heartburn Cholesterol lowering 2000(2002)* 2000 Irritable bowel syndrome in women Ischemic colitis. Drug-drug interactions Torsades de Pointes.Shiew-Mei Huang Drugs Withdrawn from the US Market due to Safety Reasons Withdrawn Approv Drug name Mibefradil Bromfenac Terfenadine Astemizole Alosetron* Cisapride Cerivastatin Use 1998 1998 1998 1999 1999 2000 2000 2001 2001 2003 2004 2005 2005 2005 1997 1997 1985 1988 1997 1993 1997 1997 1999 1993 1999 2001 2004 1975 CYP/transporter inhibitor Torsades de Pointes. 9. Drug-drug interactions Torsades de Pointes Torsades de Pointes. 23 S-M Huang pp 848-859 . 16: 89–99. 2010 2. Woodcock. Drug-drug interactions Bronchospasm Heart attack. Academic Press. complications of constipation Troglitazone Diabetes Rapacuronium Anesthesia Levomethadyl Opiate dependence Rofexocib Valdecoxib 99m Tc** Pemoline Pain relief Pain relief Diagnostic aid ADHD 2005(2006)* 2004 Natalizumab* Multiple sclerosis Huang. 2010 3. Acute liver failure Torsades de Pointes. 9. 175-176. et al.recent relabeling of drug products OPRU meeting. Huang. MD 12 .236. Drug-drug interactions. S-M. 215 . Bethesda. Clin Pharmacol Ther 87:32-36. March 28.

2011. Clin Pharmacol Ther 89(1): S40. Bethesda. March 28. Huang S-M. Clin Pharmacol Ther 89(4): 481-484 (April 2011) 25 S-M Huang Morrissey KM. et al.Shiew-Mei Huang Significant Drug Interactions Zhang L. PII-06 (February 2011) 26 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. Lesko LJ. MD 13 .recent relabeling of drug products OPRU meeting.

Bethesda. atorvastatin.accessdata.5 (C vs. rifampin” Drugs at the FDA (Promacta.November 2008. Monitor patients closely for signs and symptoms of excessive exposure to the drugs that are substrates of OATP1B1 (e.accessdata. rosuvastatin.. repaglinide. “Highlights” and “Drug Interactions”) http://www.” The following were listed as OATP1B1 substrates: “benzylpenicillin. 359: 789-799 (UK) 27 S-M Huang OATP1B1 Inhibition “Eltrombopag is an inhibitor of OATP1B1 transporter.gov/Scripts/cder/DrugsatFDA/ 28 S-M Huang Huan Applications of pharmacogenomics in drug development and regulatory review. 2011. March 28. Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily.gov/scripts/cder/drugsatfda/index. fluvastatin.fda.g. T) 6.4 (amiodarone) 1.fda.La bel_ApprovalHistory http://www.cfm?fuseaction=Search. according to SLCO1B1 rs4149056 Genotype (c. MD 14 . nateglinide. methotrexate.recent relabeling of drug products OPRU meeting.Shiew-Mei Huang Pharmacogenetics (simvastatin) -MyopathyGenomewide Association Odds ratio: 16. pravastatin.521T>C) 2.9 (CC/TT) 4. Association replicated in another 40 mg group The SEARCH Collaborative Group. N Engl J Med 2008. rosuvastatin) and consider reduction of the dose of these drugs.

01 0 60 120 180 240 300 360 Time (min) :×3 0.1 MRP2 0. July 2010 < Watanabe T. Bethesda. 2009> 29 S-M Huang BCRP and Rosuvastatin The Genetic Effects on Statins (GEOSTAT-1).subset of SPACE ROCKET N= 415. MD 15 . Yuichi Sugiyama Modified from Yuichi Sugiyama. March 28. 2010 30 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. Cir Cardiovasc Genet 3(3): 276-85.01 0.1 :×1/3 0.01 0.1 Plasma concentration (μ g/ml) Plasma concentration (μ g/ml) OATP1B1 :×1/3 PSbile 0.Shiew-Mei Huang PBPK: Application of PBPK in Clinical Pharmacology Evaluation . 2011.001 :×3 0. 328:652. Mostly White subjects Bailey K et al.1 :×1/3 0.001 0 60 120 180 240 300 360 Time (min) :×1/3 0 60 120 180 240 300 360 Time (min) 1 Plasma concentration (μ g/ml) Plasma concentration (μ g/ml) 1 Plasma concentration (μ g/ml) 1 :×3 0.1 Liver 0.1 Plasma concentration (μ g/ml) PSeff Sensitivity Analysis :×3 Plasma 0.01 0 60 120 180 240 300 360 Time (min) 0.recent relabeling of drug products OPRU meeting.001 0 60 120 180 240 300 360 Time (min) 0. JPET.01 0 60 120 180 240 300 360 Time (min) Courtesy of Dr.01 :×1 0. Optivia webinar. et al.Pravastatin PSinf 0.

org/do/serve?objId=PA146123006 Oral morphine study in pediatrics ongoing (CYP2D6/UG2B7 evaluated) http://www.g.fda.pharmgkb.gov/ct2/show/study/NCT01071499 Applications of pharmacogenomics in drug development and regulatory review. March 28. http://clinicaltrials.accessdata.Shiew-Mei Huang Labeling Example (4) Codeine & Metabolism 31 S-M Huang http://www. MD 16 ..gov/drugsatfda_docs/label/2009/022402s000lbl.recent relabeling of drug products OPRU meeting. 2011.pdf 32 S-M Huang . Bethesda.e.

MD 17 .htm Send in your comments 34 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. 2011.gov/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/ucm064982. March 28. Bethesda.recent relabeling of drug products OPRU meeting.fda.Shiew-Mei Huang Pharmacogenomic Pathway Analysis Certain CYP2C9 and VKORC1 gene variants increase risk HLAB*5701 Activated KRAS mutation confers resistance to EGFR inhibitors Prodrugs having reduced efficacy in CYP2C19 and CYP2D6 PMs vs EMs respectively Modified from Caskey. Annu Rev Med 2010. Larry Lesko 33 S-M Huang FDA Guidance for Industry Published for public comment in February 2011 http://www. 61:1-15 Æ Could These Have Been Predicted? Courtesy: Dr.

March 28.Shiew-Mei Huang Summary • Individual variations in drug response may be attributed to various intrinsic and extrinsic factors. genetics is one of the factors and needs to be considered along with other factors • It is important to assess safety. its association with the safe and effective use of drugs has been incorporated in the drug label and some tests have been incorporated into clinical practice • Challenges need to be continued to be addressed in the translation of genetic information to product labeling and clinical practice 36 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. effectiveness and dose-exposure response in various subgroups during drug development and apply the results of exposure-response to better define optimum individual dosing regimens 35 S-M Huang Summary (2) • As the pharmacogenetics/ pharmacogenomics information becomes available. MD 18 . 2011. Bethesda.recent relabeling of drug products OPRU meeting.

PBPK) is critical to optimal study design and to addressing issues related to multiple inhibitors/multiple patient factors • Various guidance documents in development will discuss premarketing evaluation of pharmacogenetics in early phase clinical studies. drug interactions.Shiew-Mei Huang • There is an urgent need for pediatric information • Collaboration is key to future successes • Application of modeling/simulation (e. others 37 S-M Huang Summary (3) Acknowledgement • Office of Clinical Pharmacology (OCP)/OTS 38 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. 2011. Bethesda. March 28..recent relabeling of drug products OPRU meeting. MD 19 .g.

fda.recent relabeling of drug products OPRU meeting. 2011.fda. Ken Thummel.gov/scripts/cder/drugsatfda/ Clinical Pharmacology Guidance for industry: http://www. Dick Brundage Iowa U Ray Hohl U Toronto Sandy Pang Indiana U David Flockhart Steve Hall NorthWestern Art Atkinson Stanford U Terry Blashke* USC Michael Neely Children’s Mercy Hospital Steve Leeder U Basel Urs Meyer U Ulm Julia Kirchheiner MPA Eva Gil Burglund U Manchester Malcolm Rowland. http://www.accessdata. March 28.gov/Drugs/ScienceResearch/ResearchAreas/Pha rmacogenetics/default.* Amin Rostami 39 S-M Huang U Tokyo Yuichi Sugiyama References FDA Drug Development and Drug Interactions Website. Bethesda.gov/Drugs/DevelopmentApprovalProcess/Develop mentResources/DrugInteractionsLabeling/ucm080499.gov/Drugs/DevelopmentApprovalProcess/DevelopmentRe sources/ucm049872.gov/Drugs/GuidanceComplianceRegulatoryInform ation/Guidances/ucm064982.fda. http://www.Shiew-Mei Huang U Wash.fda.htm Pediatric Study Review: 40 S-M Huang Huan Applications of pharmacogenomics in drug development and regulatory review.htm Genomics at the FDA: Drugs@FDA. MD 20 . Isabelle Ragueneau 2006-2011 OCP “Sabbatical” U Minn.htm http://www.fda.htm http://www.

recent relabeling of drug products OPRU meeting. Clin Pharmacol Ther 87:130.2677TT/GG c.Are We Ready?- Data from Niemi M. March 28. 2011.1236TT/CC c. January 2010 42 S-M Huang Applications of pharmacogenomics in drug development and regulatory review. Clin Pharmacol Ther 87:130. Bethesda. MD 21 .Shiew-Mei Huang Fold-Change in Plasma AUC .521CC/TT c.421AA/CC c. January 2010 41 S-M Huang Dosing Based on Transporter Genetics? .521T>C White: Black: Asian 15-20: 2 : 10-15% (BCRP) c.Effect of Transporter Genetics (OATP1B1) c.3435TT/CC Data from Niemi M.421 C>A White: Black: Asian 15-20: 0-5 : 25-35% (P-gp) c.