The Impact of Pharmacokinetics in Modern Drug Development—10 Years Later
San Francisco, CA, November 16, 2007
UCSF/AAPS- Dr. Les Benet Symposium
Drug Interactions & LabelingIssues Beyond the Font Size
Shiew-Mei Huang, Ph.D. Deputy Director Office of Clinical Pharmacology CDER, FDA Shiewmei.huang@fda.hhs.gov
Do current drug Labels communicate well critical information on drug interactions?
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Questions/comments received
Why is midazolam contraindicated in the ritonavir label? This is not practica for my patients with HIV! Why is grapefruit juice in the labeling of simvastatin but not atorvastatin? I am a psychiatrist, my patients are taking multiple drugs at the same time, the FDA labeleling is not very helpful!
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1998 1998 1998 1999 1999 2000 2000 2001 2001 2003 2004 2005 2005 2005
Drugs withdrawn from the US Market due to Safety reason:
Withdrawn
Approv
Drug name
Mibefradil Bromfenac Terfenadine Astemizole Alosetron* Cisapride Cerivastatin
Use
High blood pressure/Chronic stable angina
Risk
Torsades de Pointes; Drug-drug interactions; Acute liver failure Torsades de Pointes; Drug-drug interactions Torsades de Pointes; Drug-drug interactions Torsades de Pointes Torsades de Pointes; Drug-drug interactions Acute liver failure Rhabdomyolysis; Drug-drug interactions Bronchospasm Fatal arrhythmia Heart attack; stroke Skin reactions (SJS) Brain infection Cardiopulmonary arrest Liver failure
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1997 1997 1985 1988 1997 1993 1997 1997 1999 1993 1999 2001 2004 1975
NSAID Antihistamine Antihistamine
Grepafloxacin Antibiotics
Heartburn Cholesterol lowering
2000(2002)* 2000
Irritable bowel syndrome in women Ischemic colitis; 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
* remarketed with restricted distribution ** Technetium (99m Tc) fanolesomab
Discussions on Drug Interactions
• Publications of in vitro and in vivo drug interaction guidance documents
- http://www.fda.gov/cder/guidance/clin3.pdf (1997)
- http://www.fda.gov/cder/guidance/2635fnl.pdf (1999)
• Advisory Committee meetings
- April 20, 2003 (CYP3A inhibitor classification and P-gp inhibition) - November 18, 2003 (CYP2B6 and CYP2C8- related interactions) - [October, 2004, Concept paper published] November 3, 2004 (relevant principles of drug interactions) - [September, 2006, draft guidance published] October, 2006 (transporter based interactions)
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Draft published for public comment September 11, 2006 http://www.fda.gov/cder/ guidance/6695dft.pdf
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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Key messages
1. Metabolism, transport, drug-interaction info key to benefit/risk assessment 2. Integrated approach (in vitro and in vivo) may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling
October 2006, advisory committee meeting: http://www.fda.gov/ohrms/dockets/ac/cder06.html#PharmScience http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4248s1-index.htm
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Key messages (2)
4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses 5. Classification of CYP inhibitors and substrates can aid in study design and labeling 6. Labeling language needs to be useful and consistent (new labeling rule, effective June 2006) 8
What’s New?
CYP Enzymes
Transporters (P-gp) Decision trees- when in vivo studies are recommended per in vitro data - substrate (flux ratio) - inhibitor (I/Ki) - (inducer) No classification system recommended
A decision tree -- triggers when in vivo studies are recommended per in vitro data - Substrate (25% metab) - inhibitor (I/Ki > 0.1) - inducer (40% control) Classification of -inhibitors -substrates
Figure 1. Decision tree to determine whether an investi gational drug is an inhibitor for P-gp and whether an in vivo drug interaction study with a P-gp substrate is needed
Bi-directional transport assay
Net flux with concn of drug Determine Ki or IC50 [I]*/IC50 (or Ki) > 0.1 An in vivo interaction study with a P-gp substrate (e.g., digoxin) is recommended Net flux with concn of drug Poor or non-inhibitor
[I]*/IC50 (or Ki) < 0.1 An in vivo interaction study with a P-gp substrate is not needed
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*Alternate approach: [I]2/Ki > 10 < Lei Zhang, Nov 2007AAPS annual meeting>
Donald Rumsfeld on Knowledge
Hospital stay- cite drug interactions
As we know, There are known knowns. There are things we know we know. We also know There are known unknowns. That is to say We know there are some things We do not know. But there are also unknown unknowns, The ones we don't know We don't know.
Feb. 12, 2002, Department of Defense news briefing
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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The interplay of
transporters and
enzymes must be
considered in evaluating
potential drug-drug
interactions.
- Drug Development and
Drug Interactions
http://www.fda.gov/cder/drug/ drugInteractions/default.htm
Launched in May 2006
FDA Internet
ÆMore frequent updates- tables, models for decision-making, etc
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Drug Development and Drug Interactions
•Overview •Background Information •Tables of Substrates, Inhibitors and Inducers •CYP Enzymes •In vitro •In vivo •Examples of in Vivo Substrate, Inhibitor, and Inducer for Specific CYP Enzymes •Classification of Inhibitors •Classification of Substrates •P-gp Transporters •Major Human Transporters •Possible Models for Decision-Making •CYP-Based Drug-Drug Interaction Studies •P-gp-Based Drug-Drug Interaction Studies (updated 9/25/2006) •FDA Drug Interaction Working Group Members •Regulatory Guidance and Manual for Policies and Procedures (updated 9/25/2006) •Publications •Presentations •Advisory Committee Meetings (updated 9/25/2006) •Related Links •Contact Information
Labeling Rule
Two Parts:
HIGHLIGHTS OF PRESCRIBING
INFORMATION (HIGHLIGHTS)
TABLE OF CONTENT (CONTENT)
FULL PRESCRIBING
INFORMATION (FPI)
Effective June 2006; final labeling rule- http://www.fda.gov/cder/regulatory/physLabel/ 15 16
Labeling Rule (2)
HIGHLIGHTS - PRODUCT NAMES - WARNINGS - RECENT MAJOR CHANGES - INDICATIONS AND USAGE - DOSAGE AND ADMINISTRATION - DOSAGE FORM AND STRENGTHS
Effective June 2006; final labeling rule- http://www.fda.gov/cder/regulatory/physLabel/ 17
Labeling Rule (3)
HIGHLIGHTS (CONT’D) - CONTRAINDICATIONS - WARNINGS AND PRECAUTIONS - ADVERSE REACTIONS - DRUG INTERACTIONS - USE IN SPECIFIC POPULATIONS
http://www.fda.gov/cder/regulatory/physLabel/ 18
Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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Drug Interaction Labeling
When the metabolic pathway or interaction data results in recommendations for dosage adjustments, contraindications, or warnings (e.g., coadministration should be avoided) that are included in the BOXED WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, or DOSAGE AND ADMINISTRATION sections, these recommendations should also be included in HIGHLIGHTS.
< September 2006 guidance- http://www.fda.gov/cder/guidance/6695dft.pdf>
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Questions asked during evaluation
Drug interactions evaluated? Clinical significance (exposure-response)? Labeling language?
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Sitagliptin (Januvia®)
• Absolute %F ~ 87%; 73% excreted unchanged in urine; Renal clearance 350 mL/min; T 1/2~ 12 hours; 38% protein-binding. • Linear PK (25-400/600 mg); no food effect on PK; Cmax~ 1 uM after 100 mg dose • Metabolism by CYP3A/CYP2C8 • In vitro (effect on CYPs): - IC50 100 uM- CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4 (I/Ki <0.01- not an inhibitor) - Induction - <13% of CYP3A control (not an inducer) • In vitro: substrate of P-gp and OAT-3 (not OCT2, OAT1, PEPT1); not an inhibitor of P-gp
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Case 1
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Sitagliptin on digoxin
Digoxin+S/Digoxin
1.24 1.22 1.2 1.18 1.16 1.14 1.12 1.1 1.08 1.06 1.04
Sitagliptin (Januvia®)
• Efficacy - Preclinical data indicated 80% DPP-4 inhibition for PD effect - Phase 1 in Healthy subjects – 25-600 mg study; DPP4 inhibition-> 100 mg maintained 80% inhibition
- Phase 2: 25-100 mg BID or QD-> HbA1c - Phase 3: 100 and 200 mg QD study; HbA1c, FPG, PPG • Safety - QT prolongation: -Healthy subjects: 100 and 800 mg vs. placebo vs. Moxifloxacin; patients 100, 200 mg No effect boundary 50-200%
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Exposure-response data
AUC 100 mg
Cmax
200 mg 100 mg
200 mg
http://www.fda.gov/cder/foi/nda/2006/021995s000_MedR.pdf>
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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Fold-Change in Exposure (AUC)
Sitagliptin (Januvia®)
Exposure-response data
• Healthy subjects (n=79) 100 and 800 mg vs. placebo vs. Moxifloxacin 7-14 msec
QTcFChange from Baseline (active-placebo)
14 12 10 8 6 4 2 0 -2 0 5 10 15
4 3.5 3 2.5 2 1.5 1 0.5 0
Labeling: Dosage & Administration
Age
>65
Renal
CrCl
Moxifloxacin
8 msec
Race
Gender
Metformin
Hepatic
Child-Pugh 7-9
Cyclosporine
Control
800 mg
50-80
100 mg
Shallow “concentration- QTcF change” curve
25
100 mg
daily
30-50
50 mg daily
<30; ESRD/HD
< October 2006 sitagliptin (JANUVIA ® -Merck) labeling> http://www.fda.gov/cder/foi/label/2006/021995lbl.pdf
25
mg
daily 26
Fold-Change in AUC
Fold-Change in AUC
Labeling: Effect of Other
Drugs on Sitagliptin
2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0
Labeling: Effect of Sitagliptin on Other Drugs
2 1.8 Warfarin \ 1.6 Contrvol Rosiglitazone Glyburide 1.4 OC Digoxin 1.2 NE/EE Simvastatin Metformin 1 0.8 0.6 0.4 0.2 0
Cyclosporine
Control
600 C, 100 S Single dose
..did not meaningfully alter PK
Metformin
..meaningful interactions …not expected with other P-gp inhibitors
< Data from October 2006 sitagliptin (JANUVIA ® -Merck) labeling> http://www.fda.gov/cder/foi/label/2006/021995lbl.pdf
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Clinical Pharmacology Section
Not CYP2C8 inhibitor monitored Not Risk of Not Did not appropriately hypoglycemic OCT CYP3A meaningfully (Drug effect unknown inhibitor inhibitor alter….. Interactions) (Warnings/
minimal effect
Precautions)
Not CYP2C9 Inhibitor/
PMC
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Lapatinib (Tykerb®)
• 1500 mg daily undivided dose
• Metabolized by CYP3A (major) and CYP2C8/CYP2C19 • Ketoconzole increased exposure 3.6-fold • Carbamazepine decreased exposure by 72% • Possible inhibitor of CYP2C8 and CYP3A • I/Ki= 9.2 (CYP2C8), 5.0 (CYP3A)
Case 2
• P-gp substrate, flux ratio of 15.6 at Cmax
• inhibits P-gp (I/IC50= 1.4)
August 2007 lapatinib (Tykerb) label http://www.fda.gov/cder/foi/label/2007/022059s002lbl.pdf
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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Postmarketing Study Commitment (PMC)
•A study with midazolam to evaluate CYP3A inhibition effect at steady state dosing •A study with paclitaxel or rosiglitazone to evaluate CYP2C8 inhibition effect •A study with digoxin to evaluate P-gp
inhibition effect
• http://www.fda.gov/cder/foi/appletter/2007/022059s000ltr.pdf 31
Highlights of Prescription Information
•DRUG INTERACTIONS •TYKERB is likely to increase exposure to concomitantly administered drugs which are metabolized by CYP3A4 or CYP2C8. (7.1) •Avoid strong CYP3A4 inhibitors. If unavoidable,
consider dose reduction of TYKERB in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2)
•Avoid strong CYP3A4 inducers. If unavoidable,
consider gradual dose increase of TYKERB in patients coadministered a strong CYP3A4 inducer. (2.2, 7.2)
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Full Prescription Information
7.1 Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised. 7.3 Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised.
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Summary
- Critical drug interaction information needs to be in the “Highlights” section of the labeling - CYP-based interaction well defined in general; labeling recommendations (language and section) based on clinical significance: exposure- response relationship & benefit/risk ratio
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Summary (2)
- Measures to improve labeling
consistency have been proposed
- Transporter-based interactions have been increasingly evaluated; P-gp based interactions are among the most evaluated; results have been included in the drug label
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We need your continued input!
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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References
• Guidance for industry: Drug Interaction Studies: Study design, Data analysis and Implications for Dosing and Labeling (Issued for public comment, September 11, 2006, http://www.fda.gov/cder/guidance/6695dft.pdf). • FDA Drug Development and Drug Interactions Website; http://www.fda.gov/Cder/drug/drugInteractions/default. htm, established May 2006 • Huang S-M, Temple R, Throckmorton D, Lesko L, Clin Pharmacol Ther 2007; Feb • Huang S-M, Strong J, Zhang L, et al, J Clin Pharmacol (in press)
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Drug Interactions working group
Sophia Abraham Sayed Al-Habet Sang Chung Philip Colangelo Shiew-Mei Huang Ron Kavanagh Patrick Marroum Srikanth Nallani Nam Atik Rahman Kellie Reynolds Sally Yasuda Lei K Zhang Jerry Collins Soloman Sobel David M Green David Frucht Hon Sum Ko Toni Stifano Robert Temple Janet Norden Kenneth Thummel Gilbert Burckart (on sabbatical at FDA, 2006)
Raman Baweja Paul Hepp Lawrence Lesko Wei Qiu Xiaoxiong Wei Jenny H Zheng John Strong
Many who have provided comments on the guidance
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Shiew-Mei Huang, Les Benet Symposium, November 16, 2007, San Francisco, CA
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