Interindividual and intraindividual pharmacokinetic ... Interindividual and intraindividual pharmacokinetic

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  • Interindividual and intraindividual

    pharmacokinetic variability

    Mark J. Ratain, M.D.

    University of Chicago

    2nd International Workshop on Clinical

    Pharmacology of Anticancer Drugs

    Madrid, Spain

    September 13, 2017

  • JCI, 1988

  • Jin et al., J. Natl. Cancer Inst. 97:20-39, 2005.

    Tamoxifen Biotransformation

  • JCO, 2011

  • Metabolism of Irinotecan (CPT-11)

    CPT-11

    APC

    SN-38G

    SN-38

    CYP3A4

    CE

    UGT1A1

    N N

    O

    O

    N N

    O

    O

    O H O

    C2H5

    N N

    O

    O

    O H O

    C2H5

    H O

    N

    O

    O

    N N

    O

    O

    O H O C2H5

    H NH O

    O

    O

    N N

    O

    O

    O HO

    C2H5

    O

    C O O H

    O HHO

    0302_Irinotecan (CPT-11)

  • Irinotecan (350 mg/m2)

    pharmacokinetics and TA indel genotype (Innocenti, J Clin Oncol, 2004)

    SN-38

    AUC

    (ng*h/ml)

    SN-38G

    AUC

    (g*h/ml)

    Glucuronidation

    ratio

    6/6 (n=30)

    336168 2.01.4 6.54.0

    6/7 (n=25)

    458380 1.91.7 5.64.8

    7/7 (n=6)

    542195 1.81.3 3.62.8

    Nonparametric trend analysis, p=0.03

  • Relationship between CL and phenotypic measurement of CYP3A4.

    JoAnn Hirth et al. Clin Cancer Res 2000;6:1255-1258

    ©2000 by American Association for Cancer Research

  • Intraindividual variability of

    antiretrovirals

    (Nettles, Clin Inf Dis, 2006)

    • Lopinavir/ritonavir 24-92%

    • Nelfinavir/M8 metabolite 30-54%

    • Ritonavir 34-43%

    • Saquinavir 52-55%

  • Why is intraindividual variability of

    increasing importance in oncology?

    • Increasing use of oral drugs

    – Often with low bioavailability

    – Substrates for CYP3A

    • Increasing use of expensive drugs

    – Financial incentive to increase

    bioavailability

    • Increasing use of monoclonal antibiodies

    – May have time-dependent clearance

  • Erlotinib concentrations versus time following the 150 mg erlotinib dose (A) and the 300 mg erlotinib dose (B).

    Marta Hamilton et al. Clin Cancer Res 2006;12:2166-2171

    ©2006 by American Association for Cancer Research

  • CCR, 2010

    Focus on 23 drugs with marked (+50%) food effect

  • ©2010 by American Association for Cancer Research

    lapatinib

    nilotinib

    erlotinib

    deferasirox

    posaconazole

  • Black Box Warning for

    nilotinib

  • Nilotinib labeled to be taken

    fasting

  • In other words, if you take nilotinib

    with breakfast, you might die!!!

  • Abiraterone

  • Abiraterone (cont)

  • A prospective international randomized

    phase II study evaluating the food effect

    on the pharmacokinetics (PK) and

    pharmacodynamics (PD) of abiraterone

    acetate (AA) in men with castrate

    resistant prostate cancer (CRPC)

    Russell Szmulewitz, MD

  • Hypothesis and Design

    • Hypothesis: Lower-dose abiraterone taken

    with food will have a similar effect on CRPC as

    full-dose taken fasting. We will use serum PSA

    as a pharmacodynamic marker of abiraterone

    effect.

    Progressive CRPC • PS 0-2 • Prior keto

    stratification

    R

    STD: Abiraterone 1000mg/day fasting+ prednisone 5mg BID

    LOW: Abiraterone 250mg/day with low fat meal+ prednisone 5mg BID

    Primary Objective: PSA response at 12 weeks

  • Study demographics • 72 patients across 7 centers (6 US, 1 Singapore)

    Characteristics STD (n=36) LOW (n=36)

    Age

    Median (range)- year 71(49-83) 69(53-83)

    >75 years- no of patients /total no 10(27%) 11(31%)

    Disease location, n(%)

    Bone 25(69%) 25(69%)

    Visceral 5(14%) 5(14%)

    Prior systemic treatment for CRPC, n(%)

    0 14(39%) 12(33%)

    2-Jan 14(39%) 16(44%)

    3 or more 2(6%) 1(3%)

    Prior chemotherapy, n(%)

    0 21/36(58%) 19(53%)

    1 9(25%) 9(25%)

    2 or more 0(0%) 1(3%)

    ECOG performance status, n(%)

    0 or 1 33(92%) 33(92%)

    2 2(6%) 3(8%)

    Prostate- specific antigen

    Median (range) 48.4(0.73-1789) 48.4(1.01-1768)

    Race, n(%)

    White 26(72%) 17(47%)

    African American 5(14%) 11(31%)

    Asian 5(14%) 7(19%)

  • Primary endpoint: PSA response-Nadir

    STD (1000mg fasting) LOW (250mg fed)

    PSA50%-Nadir: STD=61%,LOW=69%, **PSA50% on COU-302=62%

  • Understanding intraindividual

    variability may create

    opportunities to monetize clinical

    pharmacology knowledge

    • Clearance of oral small molecules can be

    decreased with food or CYP3A4

    inhibitors

    • Modulation of clearance of monoclonal

    antibodies may also be feasible

    • High drug prices have created new

    “targets” for pharmacokinetic

    modulation