Pharmacokinetic and Pharmacodynamic Parameters ... Pharmacokinetic and Pharmacodynamic Considerations

  • View
    10

  • Download
    6

Embed Size (px)

Text of Pharmacokinetic and Pharmacodynamic Parameters ... Pharmacokinetic and Pharmacodynamic...

  • 10/1/19

    1

    Pharmacokinetic and Pharmacodynamic Considerations in Cancer Chemotherapy

    Indications and Dosing

    Daniel L. Gustafson, PhD Professor Shipley University Chair in Comparative Oncology Colorado State University

    Outline of Discussion • Pharmacokinetics

    • Parameters • Variability

    • Pharmacodynamics • Toxicity • Efficacy • Surrogate Measures of Response

    • Dose Normalization • Per kg, per m2 • Other dosing metrics

    • Drug Dosing of Specific Agents • Dose finding studies • Selecting the proper dose, dose interval and what to measure

    Pharmacokinetics (PK) and Pharmacodynamics (PD) How are they related?

    Dose Pharmacokinetics Drug

    Levels at Target

    Pharmacodynamics Response Genetics Body Size Environment Physiology Diet

    Genetics Environment Physiology Diet

    Through Drug Exposure at the Site of Action

    Blood

    Pharmacokinetics Chemotherapy Drug Response The pharmacokinetic parameters of a given drug are important because they are the link between dose and response as they represent a measure of drug exposure.

    Common Assumptions of Drug Therapy • Dose is related to drug exposure – Higher dose leads to proportional increase in drug exposure

    • Drug exposure is related to response – An increase in drug exposure will increase drug response, both good and bad

    • Blood/serum/plasma drug levels are a good indicator of drug exposure – Circulating levels of drug in the blood are proportional to “target tissue” drug levels

    Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response

    Pharmacokinetics Is Dose Proportional to Exposure?

    In general, drug exposure is proportional to dose. However, notice the variability in exposure across the population. Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response

    PLoS One 5:e11013, 2010

    Pharmacokinetics • The fate of a therapeutic agent when administered to a living organism • Commonly described by drug levels measured in the blood compartment

    0 1 2 3 4 5 6 10

    100

    1000

    Time (hr)

    [D ox

    or ub

    ic in

    ] s er

    um (n

    M )

    0 1 2 3 4 5 6 10

    100

    1000

    Time (hr)

    [D ox

    or ub

    ic in

    ] s er

    um (n

    M )

    Data from 28 dogs treated with Doxorubicin @30mg/m2 via a 20 minute infusion

  • 10/1/19

    2

    Pharmacokinetics IV bolus/short infusion administration of infrequent doses

    • Measured Parameters • Cmax – maximal concentration achieved • AUC – drug exposure as determined by concentration x time • Terminal Half-Life – how long it takes drug to decay in the blood

    0 1 2 3 4 5 6 10

    100

    1000

    Time (hr)

    [D ox

    or ub

    ic in

    ] s er

    um (n

    M ) Cmax

    AUC (Area Under the Curve)

    Terminal half-life (t1/2)

    Pharmacokinetics Multiple-Doses Given Frequently

    • Measured Parameters • Cmax • Tmax – time to reach Cmax • Terminal half-life – plays a role in dosing interval and accumulation • Cmin – also referred to as trough

    • Cmax is a function of dose, t1/2 and Tau

    • Cmin is a function of dose, t1/2 and Tau

    • Cavg is a function of dose, t1/2 and Tau

    • Accumulation factor is dependent on t1/2 and Tau

    • Tmax is dependent kabs and t1/2

    How can Cavg be the same but Cmin and Cmax be different?

    Pharmacokinetics Pro-Drugs

    • Many clinically-used anti-tumor agents are actually pro-drugs and need to be activated in one way or another.

    What should you actually measure?

    Pharmacokinetics Pro-Drugs

    0 1 2 3 4 5 6 1

    10

    100

    1000

    10000

    100000 IV Dosing Oral Dosing

    Time (hr)

    [C yc

    lo ph

    os ph

    am id

    e] p

    la sm

    a ( ng

    /m l)

    0 1 2 3 4 5 6 1

    10

    100

    1000

    10000

    IV Dosing Oral Dosing

    Time (hr)

    [4 -O

    H -C

    P] p

    la sm

    a ( ng

    /m l)

    Dogs receiving 250 mg/m2 cyclophosphamide either IV or PO

    Measuring the active drug is very important in this case. If you just measured the CP it would seem that you were underdosing via the PO route and would suggest dose escalating. The 4-OH-CP data tells a completely different story.

    Pharmacokinetics Cyclophosphamide PK in Cats

    0 60 120 180 240 300 360 420 480 1

    10

    100

    1000

    10000

    Time (min)

    [C yc

    lo ph

    os ph

    am id

    e] pl

    as m

    a ( ng

    /m l)

    Cyclophosphamide

    IV IP PO

    0 60 120 180 240 300 360 420 480 1

    10

    100

    1000

    10000

    Time (min)

    [4 -O

    H C

    P] pl

    as m

    a ( ng

    /m l)

    4-OH CP

    IV IP PO

    0

    5000

    10000

    15000

    20000

    A U

    C /D

    os e

    IV IP PO

    Cyclophosphamide 4-OH-CP

    PK of CP and 4-OHCP is similar in cats as 4-OHCP exposure is similar via the IV or PO route

    Pharmacokinetics Variability – Doxorubicin Exposure

    0 2 4 6 10

    100

    1000

    10000

    Time (hr)

    [D ox

    or ub

    ic in

    ] s er

    um n

    g/ m

    l

    AUC0-6hr Mean = 455 ng/mlhr Minimum = 332 ng/mlhr Maximum = 697 ng/mlhr

    Doxorubicin dosed at 30 mg/m2 in dogs shows an exposure range in 20 dogs that can vary by ~2X. In this cohort, there was no measured variable that could account for any of the variability.

    Where does the variability come from? - For doxorubicin this is a bit unclear - Inter-patient variability (CV%) ~ 24% - Intra-patient variability (CV%) ~ 18%

    Dose 1 Dose 2 0

    20000

    40000

    60000

    80000

    100000

    A U

    C (n

    g/ m

    l x m

    in )

  • 10/1/19

    3

    Pharmacokinetics Variability – Doxorubicin Exposure

    No covariates were defined in a recent Pop-PK analysis in humans although DOX and DOXol exposure correlated with hematological toxicity…. We’ll get back to this later.

    What does this mean?

    • Adjusting DOX dosing based on renal or hepatic function has not been established

    • DOX metabolism to DOXol does not correlate in any meaningful way with exposure but the combination of DOX + DOXol may be more informative than just DOX

    • DOX exposure is related to dose but high intra-patient variability makes dose adjustment difficult within a patient

    25 mg/m2 30 mg/m2 0

    10 20 30 40 50

    500 600 700 800 900

    1000 1100

    Doxorubicin Dose

    D O

    X Ex

    po su

    re se

    ru m

    AUC0-6h

    AUC/Dose

    *P=0.016

    Pharmacokinetics Variability - Vinblastine

    0 30 60 90 12 0

    15 0

    48 0

    96 0

    14 40

    1

    10

    100

    1000

    Minutes

    Vi nb

    la st

    in e s

    er um

    (n g/

    m L)

    Variability in exposure (AUC) showed a CV (%) of 60.5 and varied from 3,091 ng/mlmin to 20,743 ng/mlmin.

    PK Parameters following a dose of 2.5 mg/m2 IV bolus dose of vinblastine sulfate in dogs

    Pharmacokinetics Variability - Vinblastine

    Consequences of high variability

    0

    5000

    10000

    15000

    20000

    V in

    bl as

    tin e

    E xp

    os ur

    e Toxicity

    Efficacy with Acceptable Toxicity

    Sub-therapeuticDose PK⎯ →⎯ Exposure PD⎯ →⎯ Response

    • Higher fractions of patients fall into exposure ranges that may result in less than optimal responses and more serious toxicities

    • More complex dosing metrics are needed that attempt to reduce variability

    • Without knowledge of inter- vs. intra-patient variability, dose escalation or reduction within a patient is difficult to interpret.

    NOTE: The values shown here for toxicity and sub- therapeutic are made up and only for illustration

    Dose-Exposure-Response

    Dose Blood

    Tissues

    Tumor

    PK

    PD Toxicity

    PD Efficacy

    Response These things are related

    Drug effect is related to drug exposure… even for oncology.

    Pharmacokinetics Is Dose Related to Response?

    3.0 3.5 4 0

    20

    40

    60

    0/3

    4/16

    2/4

    Vinblastine Dose (mg/m2)

    % w

    ith G

    ra de

    II I/I

    V N

    eu tr

    op en

    ia This Phase I data from a study of single agent vinblastine in dogs provides some evidence that dose is related to toxic response (neutropenia). However, without any data with regards to exposure the power to compare within and between groups and to add a graded component to the dosing groups is lost.

    In oncology this is a tough one… Dosing and drug exposure is usually limited to not elicit a toxic response, which is presumably related to therapeutic response. In general, it is assumed that dose intensity will correlate with response.

    Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response

    Pharmacokinetics Is exposure related to response?

    Drug exposure is related to response in the most direct manner and as such being able to predict drug exposure from a given dose would be the most exact way to have a more uniform dose-response relationship acro