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AAPS Annual Meeting Powered By Docstoc
					 American Association of Pharmaceutical Scientists Annual meeting
“Why Absorption and Pharmacokinetic Models Are More Important in
                    Future Drug Development”
                November 17, 2008, Atlanta, GA


           Challenges in the
      Evaluation and Labeling of
        Drug-Drug Interactions
     - Focusing on Transporters -
                 Shiew-Mei Huang, Ph.D.
                     Deputy Director
              Office of Clinical Pharmacology
                       CDER, FDA
               shiewmei.huang@fda.hhs.gov
                                                            1
                                                                   2 Shiew-Mei Huang
<Huang S-M, Temple R, Clin Pharmacol Ther. 84(3): 287-294, 2008>
<Huang S-M, Temple R, Clin Pharmacol Ther. 84(3): 287-294, 2008>   3 Shiew-Mei Huang
   Number of published papers/patents
600                                                                          MDR1
500

400

300
                                                                             BCRP
200                                                                          OCT
                                                                             MRP2
100
                                                                             OAT
  0                                                                          OATP1B1
         76         81        86      91           96        '01       '06
                                   Year
 <Survey via Biovista; courtesy: Aris Persidis>                      4 Shiew-Mei Huang
 http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4248s1-6-FDAHuang_files/frame.htm
  Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily,
                         According to SLCO1B1 rs4149056 Genotype


                                                            OATP1B1
                                                                &
                                                            Myopathy
                                                             (80 mg
                                                           Simvastatin)




                                                                       5 Shiew-Mei Huang
The SEARCH Collaborative Group. N Engl J Med 2008;10.1056/NEJMoa0801936
Discussions on Drug Interactions

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  97      99              03           04          06
19      19              20           20          20
 Guidance                              Concept
Publication                                                      Public
                                        Paper
                                                                Workshops
            Public
                                 Advisory                Oct 2-3, 2008
                                                      (e.g.,
                                Committee          FDA/DIA Critical Path
           Workshops
                                 Meetings
                                                   Transporter Workshop)
                                     FDA Scientific Sabbatical
 -------------FDA Publications-------------
                                                                     6 Shiew-Mei Huang
    U Wash.
                 2006-2008 OCP “Sabbatical”
      Ken                                    U Toronto
    Thummel                                    Sandy
                                                Pang
    U Wash.                  U Minn.
    Isabelle                   Dick
                             Brundage           Indiana U
   Ragueneau
                                              David Flockhart
                                   Iowa U           Steve Hall
                                  Ray Hohl
    Stanford U                                 NorthWestern
   Terry Blashke*                              Art Atkinson

    USC                          Children’s Mercy
Michael Neely                         Hospital
                                   Steve Leeder




    U Basel
   Urs Meyer


           U Manchester
          Malcolm Rowland*


    * Prior to 2006
                                                                 7 Shiew-Mei Huang
Draft published for public
         comment
   September 11, 2006
http://www.fda.gov/cder/
  guidance/6695dft.pdf




             8 Shiew-Mei Huang
                           What’s New


          Metabolism, transport,
        drug-interaction info key to
          benefit/risk assessment

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
<Huang,Temple,Throckmorton,Lesko, Clin.Pharmacol.Ther. Feb 2007>
<Huang, Strong, Zhang, Reynolds, Nallani, Temple, et al, J Clin Pharmacol, June, 2008>
<Zhang, Zhang, Strong, Reynolds, Huang, Xenobiotica, July 2008>              9 Shiew-Mei Huang
   CYP Enzymes        What’s Transporters (P-gp)
   Decision trees-- New?       Decision tree—
When in vivo studies       When in vivo studies
are recommended            are recommended
per in vitro data          per in vitro data
-Substrate (25% metab)     - Substrate (flux ratio)
- Inhibitor (I/Ki > 0.1)   - Inhibitor (I/Ki)
- Inducer (40% control)    - (Inducer)

Classification of          No classification
- Inhibitors               system recommended
- Inducers
- Substrates
                                       10 Shiew-Mei Huang
Figure 1. Decision tree to determine whether an investigational 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                 Net flux    with
                       concn of drug                   concn of drug


              Determine Ki or IC50                   Poor or non-inhibitor


  [I]*/IC50 (or Ki) > 0.1             [I]*/IC50 (or Ki) < 0.1


An in vivo interaction study            An in vivo interaction study
with a P-gp substrate                   with a P-gp substrate
(e.g., digoxin) is recommended          is not needed

*Alternate approach: [I]2/Ki > 10                              11 Shiew-Mei Huang
<L Zhang, Y Zhang, JM Strong, K Reynolds, S-M Huang, Xenobiotica, July 2008>
Transporter Info
 in the Current
     Labeling

             12 Shiew-Mei Huang
                         Current Labeling*
 Transporter                   Drug Names
 P-gp                          Ambrisentan, (aprepitant),
                               clarithromycin, fexofenadine,
                               (fosaprepitant), (ixabepilone), lapatinib,
                               posaconazole, ((propafenone)),
                               ranolazine, sirolimus, tipranavir,
 OATP1B1                       Atorvastatin, [cyclospoprine], lapatinib
 OATP                          Ambrisentan
 Organic anion                 Sitagliptin
 Organic cation                Metformin, pramipexole, varenicline
 BCRP                          Lapatinib
 MRP                           (Ixabepilone)
*This is not an extensive list. Data based on a preliminary survey of electronic PDR,
October 1, 2008. Those in “( )” indicated mentioned in the labeling as not         13 Shiew-Mei Huang
 a substrate or not an inhibitor ( ), or not studied (( )) or as an inhibitor [ ] for other drugs
              IND/NDA Discussions*
 Transporter                    Recommendations
 No data on P-gp                Post-marketing commitment as P-gp
 (oncology)                     substrate or inhibitor
 OATP1B1                        Recommended study with
 substrate                      lopinavir/ritonavir
 (HIV)
 OATP1B1                        Sponsor studied rosuvastatin
 inhibitor
 CYP3A/OATP1B1                  Sponsor studied simvastatin
 inhibitor



* Not an extensive list; case examples from recent IND/NDA discussions-
courtesy of Abraham S, Booth B, Zhang L, Zhang YD                         14 Shiew-Mei Huang
         Selected efflux & uptake
      transporters in the gut wall (a),
          liver (b), and kidneys (c)




Huang S-M, Lesko LJ, and Temple R, "Adverse Drug Reactions and Pharmacokinetic Drug
Interactions", Chapter 21, Adverse Drug Reactions and Drug Interactions in Part 4,
FUNDAMENTAL PRINCIPLES: Clinical Pharmacology, “Pharmacology and Therapeutics: Principles to
Practice,” Ed. Waldman & Terzic, Elsevier (in press)                        15 Shiew-Mei Huang
   Discussions on Drug Interactions
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    7       9               3             4            6
199     199             200           200          200                              FDA Internet
                                                                                 -Drug Development
 Guidance                               Concept             Guidance                    and
Publication                                                Publication           Drug Interactions-
                                         Paper
                                  Advisory
            Public                                                 Public
                                 Committee
           Workshops                                              Workshops
                                  Meetings
                                       FDA Scientific Sabbatical
   -------------FDA Publications-------------
 http://www.fda.gov/cder/drug/drugInteractions/default.htm
                                                                             16 Shiew-Mei Huang
                  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

•FDA Drug Interaction Working Group Members

•Regulatory Guidance and Manual for Policies and Procedures

•Publications

•Presentations

•Advisory Committee Meetings

•Related Links
                                                                                         17 Shiew-Mei Huang
•Contact Information
Questions Asked during
       Review

Drug interactions evaluated?

Clinical significance of the
finding (exposure-response)?
Labeling language?
                      18 Shiew-Mei Huang
Case 1


         19 Shiew-Mei Huang
                 Rosuvastatin (Crestor®)
     –   Not extensively metabolized (10%) CYP2C9
     –   F=20%, fe= 6%
     –   Substrate for BCRP and OATP1B1*
     –   Interaction studies conducted-
   Effect of other drugs                           Effect on other drugs
   Cyclosporine; Gemfibrozil                       Warfarin
   Lopinavir/ritonavir                             Digoxin
   Fenofibrate; Antacid                            Oral contraceptives
   Erythromycin,
   Ketoconazole,
   Itraconazole, Fluconazole
(Data compiled from labeling for Crestor (rosuvastatin; AstraZeneca); Clin pharm review- S Chung;
Labeling from http://www.accessdata.fda.gov/scripts/cder/drugsatfda.          20 Shiew-Mei Huang
November 2007 labeling) * literature
                             LDL-C: % Change From Baseline
                            Rosuvastatin (Crestor®) vs Placebo
                                                   Rosuvastatin dose, mg

                                  1        2.5       5      10     20      40     80     Placebo
                            n=   14        15       18      17     17      34     31        31
                            0
  % change from baseline




                           -10                                                               -4
                           -20
                           -30
                           -40    -33
                           -50              -40      -43
                           -60                              -50
                                                                    -53
                           -70                                              -62
                                 Baseline characteristics                          -65
                           -80     Mean age: 56 yr
                                   Mean LDL-C: 190 mg/dL
< .001 vs placebo; data presented as LS mean ± SE; Trials 8 and 23 Pooled (Wk 6)

 <Crestor® Clinical Development Efficacy, Dr. James Blasetto, MD, MPH, AstraZeneca
 July 9, 2003>                                                   21 Shiew-Mei Huang
 http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs
          Incidence of CK elevations and
            myopathy in phase II/III
                      (mg)                CK>10xULN                     MYOPATHY
                                                                        (all cases)
  Baycol              0.4                 1.6%                          1.0-1.6%
                      0.8                 2.1%                          0.9-1.0%

                      Pbo                 0%                            0%
   Rosuva             5                   0.4%                          0.2%
                      10                  0.2%                          0.1%
                      20                  0.2%                          0.1%
                      40                  0.4%                          0.2%
                      80                  1.9%                          1.0%
   All marketed
   STATINSa     5-80                      0.03-0.9%                     0-0.5%
  Data from Tables 10, 11 FDA briefing packet
<Crestor® William Lubas, MD, PhD, CDER, FDA, Advisory Committee meeting, July 9, 2003>
http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs
                                                                         22 Shiew-Mei Huang
     Plasma rosuvastatin concentrations by
           dose and in patients with
        rhabdomyolysis or renal toxicity




<Crestor® William Lubas, MD, PhD, CDER, FDA, Advisory Committee meeting, July 9,
2003> http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs
                                                              23 Shiew-Mei Huang
     Dosage and Administration
- Approved 5-40 mg
                      5                     40            80



                               Efficacy Curve
      Response (PD)




                          Safety (Adverse Effect) Curve




                                  Dose
                                [Exposure]


                                                               24 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
                                                                             25 Shiew-Mei Huang
<Huang S-M, Temple R, Clin Pharmacol Ther. 84(3): 287-294, 2008>
Case 2


         26 Shiew-Mei Huang
                                                         27 Shiew-Mei Huang
<http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf>
                                                         28 Shiew-Mei Huang
<http://www.fda.gov/cder/foi/label/2007/022128lbl.pdf>
There is a need
 to understand
  interactions
among multiple
   (>2) drugs
            29 Shiew-Mei Huang
                                            Multiple inhibition
                                                                       Maximum change by CYP1 and 2
    AUC change of drug (fold)

                                 25.0
   AUC change of a drug (fold)

                                                                                     inhibition

                                 20.0


                                 15.0                 Potential surprise!

                                            Change by CYP 2         Prediction from CYP 1
                                 10.0          inhibition            and CYP2 inhibition


                                  5.0                                                       Change by CYP 1
                                                                                               inhibition
                                  0.0
                                        0       0.2           0.4     0.6          0.8             1
                                                      Fractional CL by CYP 1
                                                                                  Relative contribution of
                                                                                 Relative contribution of CYP 1
                                                                                  CYP 1 and 2 is equal.
                                                                                         and 2 is equal.

Thummel K, Chung S, et al, ASCPT, poster II-77, March 23, 2007;
Chung S, Thummel K, et al, AAPS, November, 2007                                             30 Shiew-Mei Huang
                           Combination of CYP and
                         transporter interactions
                  20                                                    Mechanism of
Repaglinide AUC




                  18                                                    Interactions:
 (fold-change)




                  16

                                                                        Gemfibrozil and
                  14
                  12
                  10                                                    its glucuronide
                   8                                                    metabolite
                   6                                                    inhibit
                   4                                                     - CYP2C8
                                                                         - OAPT1B1
                   2
                   0

                           il                 le               il
                         oz                 zo             r oz
                 ib    r                ona          mf +
                                                          ib
              mf                     rac           Ge             ole
            Ge                  It                               z
                                                            cona
                                                     I tr a
                                                                            31 Shiew-Mei Huang
 < Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51>
 There is a need
to use an optimal
  study design

              32 Shiew-Mei Huang
                                QD400 vs SD400 Ketoconazole on AUCR
                               MD (QD) 400 vs SD400 Ketoconazole on AUCR
                                                                                   t1/2<21 hr & F<0.88, AUCRQD400/AUCRSD400 <1.97

                                                                                                                                       Alprazolam
                                                                                      1.97 (3.3/1.7)

                            2.00                                                                                                       T1/2=12 hr
                                                                                                                                       High F
                                                               1.73 (3.5/2.0)                              1.83 (4.5/2.5)
      AUCRQD400/AUCRSD400




                            1.80                                                                                      1.70 (6.3/3.7)


                            1.60



                            1.40           1.34 (4.0/3.0)



                            1.20
                                                                       t1/2 <5.3 hr & F<0.42 AUCRQD400/AUCRSD400 <1.25
                               1.06 (6.8/6.4)


                                                               1.22 (t1/2=5.3 hr, F=0.42)
  Midazolam 1.03 (10.0/9.6)
           0.80                                                                                                                    1.26 (55.8/44.3)

  T1/2=1.9 hr                            0.60                                                          1.20 (57.7/48.6)
  F=0.32                                1.02 (13.5/13.2)
                                                                   1.05 (18.4/17.5)
                                               0.40
                                       F                                           1.07 (65.3/61.2)                                20
                                                       0.20                                                      15
                                                                                               10
                                                                          5
              t1/2<2.7 hr & F<0.2                 AUCRQD400/AUCRSD400 < 1.05
                                                             0
                                                                1.00 (100.4/100.2)
                                                                                                t 1/2 (hr)
Zhao, P, Ragueneau I, Zhang L, Strong, JM, Reynolds, K, Levy, R, Thummel, K,
Huang, S-M, “Quantitative evaluation of pharmacokinetic inhibition of CYP3A
substrates by ketoconazole”, oral presentation at the ASCPT annual meeting, March
2009, National Harbor, MD; manuscript in press (J Clin Pharmacol) 33 Shiew-Mei Huang
                                             BID200 vs QD400 Ketoconazole on AUCR
                                                         F<0.88 & t <21hr: AUCR     /AUCR    <1.55                          1/2                             BID200   QD400
                              BID vs. QD (total 400 mg) Sustained inhibition of CL by BID200
                                                                         1.52
                                                                         1.52                                        1.55
                                                                                                                     1.55
                                                                         t1/2=12 hr
                                                                         t1/2=12 hr                                  t1/2=21 hr
                                                                                                                     t1/2=21 hr
                         1.60
                         1.60
                                                                         F=0.88
                                                                         F=0.88                                      F=0.88
                                                                                                                     F=0.88
                                                  1.41
                                                  1.41
                                                  t1/2=5.3 hr
                                                  t1/2=5.3 hr
                                                                                                                                  1.47
                                                                                                                                  1.47
                                                                                                                                  t1/2=21 hr
                                                                                                                                  t1/2=21 hr
      AUCRBID200/AUCRQD400

                                                  F=0.88
                                                  F=0.88
                                                                                                                                  F=0.60
                                                                                                                                  F=0.60
                             1.40
                             1.40
                                                                                                                                               1.39
                                                                                                                                               1.39
                                                                                                                                               t1/2=22 hr
                                                                                                                                               t1/2=22 hr
                                                                              1.24
                                                                              1.24                                                             F=0.42
                                                                                                                                               F=0.42
                                                                              t1/2=5.3 hr
                                                                              t1/2=5.3 hr
                             1.20 1.11
                             1.20 1.11                                        F=0.42
                                                                              F=0.42
                                    t1/2=1.4 hr
                                    t1/2=1.4 hr
                                    F=0.88
                                    F=0.88
                                                                                                                  F<0.42 and t1/2<5.3 hr:
                             1.00
                             1.00                                                                                 AUCRBID200/AUCRQD400 <1.25
                                                                                                                  Marginal improvement by BID200
                                              0.98
                                              0.98
                                              t1/2=1.4 hr
                                              t1/2=1.4 hr
                             0.80
                             0.80             F=0.60
                                              F=0.60
                                                                                                                                                    0.90
                                                                                                                                                    0.90
                                                           0.91
                                                           0.91                                                       0.88
                                                                                                                      0.88                          t1/2=22 hr
                                                                                                                                                    t1/2=22 hr
                                                                                                                      t1/2=13 hr
                                                                                                                      t1/2=13 hr                    F=0.04
                                                                                                                                                    F=0.04
                                                           t1/2=1.4 hr
                                                           t1/2=1.4 hr
                                    0.8
                                    0.8                    F=0.42
                                                           F=0.42                              0.81
                                                                                               0.81                   F=0.04
                                                                                                                      F=0.04
                                                                                               t1/2=5.3 hr
                                                                                               t1/2=5.3 hr
                                            0.6
                                            0.6                                                F=0.04
                                                                                               F=0.04
                                                     0.4
                                                     0.4                         0.65
                                                                                 0.65                                                                 20
                                                                                                                                                      20
                                          F                   0.2
                                                              0.2                t1/2=1.4 hr
                                                                                 t1/2=1.4 hr
                                                                                                             10
                                                                                                             10
                                                                                                                                  15
                                                                                                                                  15
                                                                                 F=0.04
                                                                                 F=0.04
                                                                                               5
                                                                                               5
                                                                          0
                                                                          0

  F=0.04 & t1/2=1.4 hr: AUCRBID200/AUCRQD400 = 0.65                                                               t 1/2 (hr)
                                                                                                                    1/2
  “1st Dose Effect” by 400 mg

Zhao, P, Ragueneau I, Zhang L, Strong, JM, Reynolds, K, Levy, R, Thummel, K,
Huang, S-M, “Quantitative evaluation of pharmacokinetic inhibition of CYP3A
substrates by ketoconazole”, oral presentation at the ASCPT annual meeting, March
2009, National Harbor, MD; manuscript in press (J Clin Pharmacol) 34 Shiew-Mei Huang
           Summary
- Transporter-based interactions have
  been increasingly evaluated; P-gp-
  based interactions are among the
  most evaluated; others include
  OATP, OCT, OAT, BCRP
  * in vitro methods and in vivo study
    triggers discussed at a DIA/FDA
    Critical Path workshop (Oct 2008)
                             35 Shiew-Mei Huang
          Summary (2)
- Labeling recommendations
  (language and section) are based on
  clinical significance: exposure-
  response relationship & benefit/risk
  ratio
- Study design a critical factor to
  consider- modeling and simulations
  can help provide optimal designs

                              36 Shiew-Mei Huang
          Summary (3)
- Efforts in development/evaluation of
models predicting the extent of drug
interactions ongoing at the FDA
 * in vitro to in vivo
 * single pair to multiple interactions
  - multiple CYP inhibitors
  - multiple modulators
     (CYP/transporter inhibition/induction)
   - effect of other metabolizing enzymes
   - effect of genetics
                                 37 Shiew-Mei Huang
                               Summary (4)
• Collaboration is key to future successes

               Enhance regulatory             Utilize
               decision making                opportunities
  FDA                                         presented by      NIH/Academia
                                              science



                                PARTNERING




 HMOs           Improve
                                             Expedite medical   INDUSTRY
                                             product
                patient care                 development
                                             process


S Buckman, S-M Huang, S Murphy, Clin Pharmacol & Ther,
81(2): 141-144, Feb 2007 (figure 1; adapted from figure
supplied courtesy of RM Long, NIH)                                38 Shiew-Mei Huang
                              Drug Interactions
                              working group

Sophia Abraham         Sayed Al-Habet     Raman Baweja
Sang Chung             Philip Colangelo   Paul Hepp
Shiew-Mei Huang        Ron Kavanagh       Lawrence J Lesko
Patrick Marroum        Srikanth Nallani   Wei Qiu
Nam Atik Rahman        Kellie Reynolds    Xiaoxiong Wei
Sally Yasuda           Lei K Zhang       Jenny H Zheng
Soloman Sobel        John Strong Derek Zhang Ping Zhao
David M Green           David Frucht
Hon Sum Ko              Toni Stifano
Robert Temple           Janet Norden
Kenneth Thummel*        Gilbert Burckart
Isabelle Ragueneau *
*(on sabbatical at FDA)
Many who have provided comments on the guidance
                                                39 Shiew-Mei Huang
    References
•    FDA Drug Development and Drug Interactions Website;
     http://www.fda.gov/Cder/drug/drugInteractions/default.
     htm, established May 2006

•    Huang S-M, Temple R, Is this drug/dose for you?
     Impact and consideration of ethnic factors in global drug
     development, regulatory review and clinical practice. Clin
     Pharmacol Ther 2008; September

•    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
     2008; June

•    Zhang L, Zhang Y, Strong J, Reynolds K, Huang S-M,
     Xenobiotica 2008; July                  40 Shiew-Mei Huang