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					Modeling and Simulation Approaches for Clinical DDI Predictions:
       Current Industry Use and Regulatory Perspective
                    ASCPT Annual Meeting
                        March 18, 2010
                         Atlanta, GA


  Regulatory Perspective of
   Modeling and Simulation
Approaches to DDI Prediction
               Shiew-Mei Huang, PhD
                  Deputy Director
        Office of Clinical Pharmacology, OTS
    Center for Drug Evaluation and Research, FDA
            Shiewmei.huang@fda.hhs.gov       S-M Huang
      Drug-Drug Interactions is One of Many
    Factors Affecting Drug Exposure/Response

                                             It is critical to
                                             evaluate how these
                                             factors affect drug
                                             response

                                             Ultimate goal
                                             Optimal dosing for
                                             patients with these
                                             individual factors
Huang S-M, Temple R, Is this the Drug or Dose for you? Clin Pharmacol
Ther 84: 287-294, 2008
FDA Clinical Pharmacology guidance: http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/ucm064982.htm       S-M Huang
     Comparative exposure and dose recommendation
        in subgroups with various patient factors




   Current practice: Adjust the dose to achieve
   similar systemic exposure
(Data compiled from labeling for Crestor (rosuvastatin; AstraZeneca);
Labeling from http://www.accessdata.fda.gov/scripts/cder/drugsatfda.); November 2007 labeling
<Huang S-M, Temple R, Clin Pharmacol Ther. 84(3): 287-294, 2008>                   S-M Huang
    Evaluation of Multiple Interactions
         or Multiple Impairments

  “There may be situations when an
  evaluation of the effect of multiple CYP
  inhibitors on the drug can be
  informative.”
  “We encourage the study sponsors
  to use modeling and simulation to
  determine the best dosing strategy”
CDER Draft Guidance for Industry “Drug Interaction Studies —
Study Design, Data Analysis, and Implications for Dosing and Labeling”,
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInforma
tion/Guidances/UCM072101.pdf
                                                                                 4
Huang S-M, Lesko, LJ, J Clin Pharamcol 49:370, 2009                  S-M Huang
Selected efflux & uptake transporters in
the gut wall (a), liver (b), and kidneys (c)
                               OATP: Organic Anion        •         OCT2: Organic Cation
                                 Transporting Polypeptide           Transporter 2
                                                          •         OAT1/3: Organic
                                                                    Anion Transporter 1/3




P-gp: P-glycoprotein
 Liver, Intestine, Kidney, Brain
BCRP: Breast Cancer Resistant Protein
 Liver, Intestine, Kidney, Brain
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, 2009                                   S-M Huang
 Development of PBPK Models
-Incorporating Population Variability Data-




                                     Huang S-M, Temple R, Clin Pharmacol
                                     Ther 84: 287-294, 2008



User Manual of PK.Sim (V4.1), 2009                       S-M Huang
                                                                     6
  Regulatory Review Questions
    (Application of PBPK Modeling)
- A study has been conducted. Do we need
  a second study with an optimal design?

- An inhibition study has been conducted.
  Can we waive an induction study?

- An inhibition study has been conducted
  with one route of administration. Can we
  waive a study with a different route?
                                                7
                                    S-M Huang
Regulatory Review Questions (2)
          (Application of PBPK Modeling)
- In vitro data suggested the drug is an inhibitor.
  Can we waive an in vivo inhibition study because
  the parent drug has a short t1/2?
- Results of individual studies on renal impairment
  and drug interactions are available; Is an
  interaction study in renal impairment needed?

  For more detailed descriptions of review cases,
  see poster III-15 (Zhao P, et al, Saturday,
  March 20, 2010)
<Zhao P, Zhang L, Lesko L, Huang S-M,                     8
Clin Pharmacol Ther 87: S72, February 2010>   S-M Huang
                            Case 1
“What is the best study design with a
 CYP3A inhibitor, either ketoconazole
 or itraconazole?”

- A study was conducted with 200 mg
  QD, do we need a second study with
  400 mg QD or 200 mg BID?
- Why isn’t a single dose ketoconazole
  sufficient for evaluation of CYP3A
  inhibition?
 Oo C, Chen YC, J Clin Pharmacol, 49: 368-369 February 2009

                                                                          9
                                                              S-M Huang
                                                              Case 1 (cont’d)
                                    MD (QD) 400 vs SD400 Ketoconazole on AUCR
                                                                                     t1/2<21 hr & F<0.88, AUCRQD400/AUCRSD400 <1.97

                                                                                      1.97 (3.3/1.7)                                   Alprazolam
                                                                                                                                       t1/2=12 hr
                            2.00                                                                                                       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)

                                                                       t1/2 <5.3 hr & F<0.42 AUCRQD400/AUCRSD400 <1.25
                            1.20

                               1.06 (6.8/6.4)


                                   0.80                                                                                            1.26 (55.8/44.3)
Midazolam                            1.03 (10.0/9.6)
                                          0.60                                                         1.20 (57.7/48.6)
t1/2=1.9 hr                              1.02 (13.5/13.2)
F=0.32                                           0.40              1.05 (18.4/17.5)
                                       F                                           1.07 (65.3/61.2)                                20
                                                       0.20                                                      15
                    t1/2<2.7 hr & F<0.2 AUCRQD400/AUCRSD400 < 1.05
                                                         5
                                                                                               10
                                                                    1.00 (100.4/100.2)
                                                               0
                                                                                                t 1/2 (hr)

P Zhao, I Ragueneau, L Zhang, JM Strong, K Reynolds, R Levy, K Thummel, S-M Huang, “Quantitative
evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole”, ASCPT annual meeting,
March 2009, National Harbor, MD; J Clin Pharmacol, February 2009                   S-M Huang
                                                                                Case 1 (cont’d)
            BID 200 vs QD 400 Ketoconazole on AUCR
                                                                                                                                          No KTZ_Hepatic
                                                                                                                                          KTZ 400 mg QD
                                                            80




                     Mean hepatic CL'int_CYP3A4 (L/hr)
                                                                                                                                          KTZ 200 mg BID

 Mean Liver                                                 70                                                                            60% Baseline_Hepatic

 CL’int,CYP3A                                               60


 =76 L/hr
                                                            50

                                                            40
                                                            30

                                                            20
QD400 achieved                                              10
maximal inhibition                                           0
but returned close                                                0   24   48   72   96   120   144   168   192   216   240   264   288    312    336    360
                                                                                                                                                                    BID200 generally
to baseline before                                                                                    Time (hr)
                                                                                                                                                                    maintained >40%
the next dose                                                                                                                             No KTZ_Intestinal
                                                                                                                                          KTZ 400 mg QD             inhibition
                     Mean intestinal CL'int_CYP3A4 (L/hr)




                                                            0.7
                                                                                                                                          KTZ 200 mg BID
                                                            0.6                                                                           60% Baseline_Intestinal

                                                            0.5
  Mean                                                      0.4
  Intestine                                                 0.3
  CL’int,CYP3A                                              0.2
  =0.64 L/hr                                                0.1

                                                             0
                                                                  0   24   48   72   96   120   144   168   192   216   240   264   288     312   336    360
                                                                                                      Time (hr)




P Zhao, I Ragueneau, L Zhang, JM Strong, K Reynolds, R Levy, K Thummel, S-M Huang,
J Clin Pharmacol, February 2009      S-M Huang
        Case 1 (cont’d)
“What is the best study design with
ketoconazole, as a CYP3A inhibitor?”
• For drugs with short t1/2 and low %F
   single dose, 400 mg of ketoconazole is
sufficient
• For drugs with longer t1/2 and high %F
   multiple doses (BID), 200 mg of
ketoconazole would provide optimal inhibition

   Review available study data in making
further recommendations
                                                12
                                    S-M Huang
                  Case 2
  “An inhibition study has been conducted
   with one route. Can we waive a study
   with a different route?”
- Sildenafil (Revatio) injection indicated
  for pulmonary arterial hypertension
- Sildenafil has an oral F of ~40%
- Sildenafil is a sensitive CYP3A substrate
  with many interactions described in the
  (Revatio) tablet and (Viagra) tablet labeling
- Ritonavir (500 mg BID) increased AUC of
  sildenafil (100 mg single oral dose) 11-fold     13
                                       S-M Huang
                 Case 2 (cont’d)
- Using PBPK simulations, the sponsor
  concluded that the extent of interaction
  with CYP3A inhibitors was markedly
  reduced when sildenafil was given by
  oral compared to IV (simulated AUC ratios
  of 9.8 vs. 3.5)

- FDA reviewer conducted PBPK simulations,
  results were similar to the sponsor’s
  (AUC ratios of 7.2-8.8 vs. 2.7)

<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022473s000_ClinPharmR.pdf>
                                                                              14
<Clinical Pharmacology Review 5.3, page 26, October 2009 by P Zhao> S-M Huang
                 Case 2 (cont’d)
 - Literature data on effects of CYP3A
   inhibitors on other CYP3A substrate
   (midazolam) were reviewed

                                                    AUC Ratio
      Midazolam                                     Oral    IV
  + clarithromycin                                   7.0    2.7
  + ketoconazole (200 mg)                           11      3.4
  + ketoconazole (400 mg)                           15      4.2
- Reviewer provided comments on limitations
  of the model
<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022473s000_ClinPharmR.pdf>
                                                                            15
<Zhao P, page 26>                                                 S-M Huang
                  Case 2 (cont’d)
           Labeling for Revatio (sildenafil)
               Tablets and Injection
HIGHLIGHTS -Warnings and Precautions-
   Use with ritonavir and other potent CYP3A
inhibitors: Coadministration not recommended
Clinical Pharmacology: Pharmacokinetics:
Ritonavir and other CYP3A inhibitors
   REVATIO injection: Predictions based on a
pharmacokinetic model suggest that drug-drug
interaction with CYP3A inhibitors will be less
than those observed after oral sildenafil
administration
<REVATIO labeling: Drugs@FDA; November 2009:                                  16
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022473lbl.pdf> Huang
                                                                     S-M
                                     Case 3
    Are Drug interactions a Concern in Hepatic or
       Renal Impaired Patients? (Rivaroxaban)
                          Severe (<30 mL/min)                          1.6
   Renal
   Impairment             Moderate (30—50 mL/min)                     1.5

                          Mild (50-80 mL/min)                         1.4

                                                        1.0     1.5          2.0   2.5         3.0

                           Child-Pugh B
   Hepatic                                                                         2.3
   Impairment              Child-Pugh A                        1.2
                                                                                                     ?
                                                        1.0     1.5          2.0   2.5         3.0

                           Ritonavir                                                     2.5
   Drug Interactions
                           Ketoconazole                                                  2.6

                                                       1.0
                                                         1.0    1.5
                                                                 1.5        2.0
                                                                            2.0    2.5
                                                                                   2.5     3.0
                                                                                          3.0

                                                   Change in AUC Relative to “Normal”
Adapted from C Tornoe, Advisory committee meeting, March 2009                         17
http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4418s1-06-FDA-Tornoe.pdf S-M Huang
       Consequences of Renal impairment
              on Drug Disposition




< Nolin TD et al, Clin Pharmacol Ther. June 2008>
< Dreisiach A, Clin Pharmacol Ther. November 2009>
                                                     S-M Huang
            Table 1. Comparative systemic exposure and corresponding starting (and
            maintenance) dose recommendation in subgroups with various renal
            impairment (Data compiled from the FDA drugs@fda website
            (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/)

                            ADME    a        Renal Function          Fold-Change                                    Initial       Daily
                                             (mL/min) b              in exposure (AUC)                              Dose          Dose

            paliperidone    fe=60%           Clcr > 80                                        1-fold(control)       6 mg          3-12 mg
                                             Clcr 50-80                                       1.5-fold (mild)       3 mg          3-6 mg
Renal




                                             Clcr 10-50                                       2.6-fold (moderate)   1.5 mg        1.5-3 mg
                                             Clcr 10-50                                       4.8-fold (severe)     1.5 mg        1.5-3 mg
                                             c


            telbivudine     fe=40%           Clcr > 50                                        1-fold (control)                    600 mg Q24H
                                             Clcr 30-49                                       1.9-fold (moderate)                 600 mg Q48H
                                             Clcr <30                                         3.4-fold (severe)                   600 mg Q72H
                                             ESRD                                             7-fold (ESRD)                       600 mg Q96H
            rosuvastatin    fe=6%            Clcr > 80d                                       1-fold (control)      10-20 mg      5-40 mg
Non-Renal




                            F=20%            Clcr >30                                         1-fold (mild)         10-20 mg      5-40 mg
                                             Clcr >30                                         1-fold (moderate)     10-20 mg      5-40 mg
                                             Clcr <30                                         3-fold (severe)       5 mg          5-10 mg
            telithromycin   fe=13%                                                            1-fold (control)                    800 mg QD
                            F=57%            Clcr <30                                         1.9-fold (severe)                   600 mg QD
                                             Clcr<30f                                         4-5 fold (severe)e                  400 mg QD
                                                                      0 1 2 3 4 5 6 7 8
        a fe: fraction of an oral dose excreted unchanged in the urine; F= % absolute oral bioavailability
        b:Estimated   by the Cockcroft-Gault equation
        c: not recommended in Clcr<10
        d:in mL/min/1.73M2
        e: patients also taking ketoconazole
        f: patients also with hepatic impairment




 <Huang S-M, Temple R, Xiao S, Zhang L, Lesko LJ, Clin Pharmacol Ther. November 2009>

                                                                                                                              S-M Huang
                                              Case 3 (cont’d)
                                                 Plasma (body-
Rivaroxaban                                   liver): (Vss – VhKP)
                                                                                    Qpv
                                                                                                         FaFGka
CLr = 4 L/h   Qhv                               CLr                            Qha    Portal vein, Vpv             Gut Lumen
CLh= 6 L/h
(CYP3A,                                            Liver, Vh
                                                                                     Qpv                          10 mg
CYP2J2,
others)
                                                 CL′int,H

                                              Observed human PK data: Kubitza, CPT, 2005
                                    140
                                    120                                               Observed
               rivaroxaban (ug/L)




                                    100                                               simulated

                                     80
                                     60
                                     40
                                     20
                                     0
                                          0         4          8      12       16         20      24

              No inhibition                                        time (hr)


                                              Simulation with SAAM II                                                  S-M Huang
                                      Plasma (body-               Qpv
                                                                          Ketoconazole inhibition
Rivaroxaban                        liver): (Vss – VhKP)
                                                                                       FaFGka
 CLr = 4 L/h           Qhv           CLr                     Qha    Portal vein, Vpv             Gut Lumen
 CLh= 6 L/h                  X?
 (CYP3A,                                Liver, Vh                                               10 mg
 CYP2J2,                                                           Qpv
 others)                              CL′int,H
                              X
                                     Plasma (body-             Qpv
Ketoconazole                      liver): (Vss – VhKP)
                                                                                       FaFGka
Ki_CYP3A4: 15 nM
Ki_CYP2J2: 2 μM
                 Qhv                CLr                     Qha    Portal vein, Vpv              Gut Lumen


Ki,Kidney ??                           Liver, Vh
                                                                  Qpv                       400 mg
Assume
Ki,CYP3A4= Ki,Kidney
                                      CL′int,H

    Simulated KTZ inhibition of CYP                                      Operating [KTZ]
                                                          Dynamic [I]u,tissue            Static [I]u,max *
    Predicted AUC Ratio (CYP only)                                  1.2                          1.6
    Predicted AUC Ratio (CYP & Renal)                               1.8                          3.4
    Observed AUC Ratio                                                            2.6
                                                                     * Kanamitsu et al, Pharm Res 2000
 Zhao et al, ASCPT LBIII-2 Poster, Atlanta, 2010                                                  S-M Huang
       KTZ + Renal Impairment (±reduced hepatic function)
                                     Plasma (body-                 Qpv
Rivaroxaban                       liver): (Vss – VhKP)
                                                                                        FaFGka
 CLr = 4 L/h          Qhv           CLr with RI               Qha    Portal vein, Vpv             Gut Lumen
 CLh= 6 L/h                 X?
 (CYP3A,                               Liver, Vh                                            10 mg
                                                                    Qpv
 CYP2J2,
 others)                             CL′int,H with RI ?
                             X
                                    Plasma (body-
Ketoconazole                     liver): (Vss – VhKP)
                                                                 Qpv
Ki_CYP3A4: 15 nM                                                                        FaFGka
Ki_CYP2J2: 2 μM  Qhv               CLr                       Qha    Portal vein, Vpv             Gut Lumen

Ki,Kidney ??                          Liver, Vh                                             400 mg
Assume                                                             Qpv
Ki,CYP3A= Ki,Kidney                  CL′int,H

 Simulated AUCR caused by combined KTZ inhibition (liver and kidney) and RI
                                                                         ↓ in GFR
                                           0%              25%             50%              75%              90%
  RI had no effect on CLh                 1.0            1.9, 3.6        2.0, 3.7         2.1, 3.9      2.2, 4.1
      RI decreases CLh                1.8, 3.4           2.0, 4.0        2.5, 4.8         3.2, 5.9      4.0, 6.8

  For [I]: dynamic [KTZ]u,tissue,or static [KTZ]u,max                                             S-M Huang
                                                                                 Case 4
                                        Inhibition effect for specific genotypes
    Pop 1: CYP2C9 EM; Pop 2: CYP2C9 PM,
                                                                                                     7-OH Warfarin                                          EM (*1/*1)            PM (*3/*3)
    M/F=1.0; Age 20-40 yr
    S-warfarin: SD 10 mg on day 1                                                               CL’
                                                                                                CL’int (uL/min/pmol CYP)                                       0.034                  0.005
    Sulfaphenazole: QD 2000 mg 5 days
                                                                                                                                                                      Using SimCYP® V8.20
     ___ EM Control                                                _ _ _ EM +Inh.                    ___ EM Control
     ___ PM Control                                                _ _ _ PM +Inh.                    ___ PM Control

                                         Mean Systemic Concentration in Plasma of S-                                                        Mean Values of Systemic Concentration in Plasma
                                        Warfarin with and without Interaction over Time                                                              of Sulfaphenazole over Time

                                     1.20                                                                                                 2.50




                                                                                                          Systemic Concentration (mg/L)
     Systemic Concentration (mg/L)




                                     1.00                        PMI/PM=1.1                                                               2.00
                                     0.80
                                                PM/EM=3.8
                                                PM/EM=3.8                                                                                 1.50
                                     0.60

                                     0.40
                                                                   EMI/EM=1.9                                                             1.00


                                     0.20                                                                                                 0.50

                                     0.00                                                                                                 0.00
                                            0     24        48         72        96       120                                                    0     24        48          72         96     120
                                                         Time - Substrate (h)                                                                                  Time - Inhibitor (h)



                                                  Substrate                                                                                             Inhibitor
     Which population needs dose adjustment?
<Zhao P, Zhang L, Lesko, L, Huang S-M,
LOL presentation, Merrimac, WI, September 2009>                                                                                                                            S-M Huang
             Summary
• PBPK modeling and simulation tools are
  useful and increasingly being used to
  optimize study design to address issues
  related to drug metabolism/excretion, and
  drug-drug interactions
• PBPK submissions include pathway
  characterization, model building, simulation
  of known and unknown in vivo scenario(s)

• FDA has reviewed more than a dozen cases
  of drug interaction evaluations using PBPK
  M&S from 2008-2009                  S-M Huang
           Summary (2)
• Limitations have resulted from incomplete
  characterization of the clearance pathway
  of the study drug and/or probe drug
  - may impact the prediction magnitude
    when multiple impairments exist
• PBPK modeling and simulations have strong
  utility, and have been applied to the
  evaluation of complex drug interactions
  involving patients with varying genotypes
  and organ functions
                                    S-M Huang
   “There is an unprecedented
   opportunity in the next few
decades to make major advances
in the life sciences and medicine
       through simulation.”


                  -- Sangtae Kim, PhD
Lead author, FDA Science Board Report
  Information Technology Subcommittee
                              S-M Huang
             Acknowledgements
•   Ping Zhao                OCP Scientific Interest Group
                             Using PBPK to Study Complex
•   Lei Zhang                Drug Interactions (PBPK-SIG)
•   Kellie Reynolds      -   Formed March 2009;
•   Larry Lesko          -   Steering committee: Ping Zhao,
•   K.Sandy Pang             Lei Zhang, Joe Grillo
                         -   Sponsor: Shiew-Mei Huang

    Office of Clinical Pharmacology/OTS
    Brian Booth, Satjit Brar, Julie Bullock, Young
    Moon Choi, Joe Grillo, Pravin Jadhav, Qi Liu, Raj
    Madabushi, Young J Moon, Padmaj Mummaneni,
    Michael Pacanowski, Atiqur Rahman, Sandra
    Suraez, Christopher Tornoe, Gene Williams, Ta-
    Chen Wu, Lillian Zhang, Issam Zineh, and others
                                                   S-M Huang
S-M Huang

				
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