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    Concept of Therapeutic Drug Monitoring TDM

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    Walaa Yousef
    Therapeutic drug monitoring (TDM) involves measuring drug concentrations in biological fluids and interpreting those concentrations based on the drug's pharmacokinetics, dosing history, and the patient's condition. TDM is indicated for drugs with a narrow therapeutic index, significant pharmacokinetic variability between patients, and an established relationship between concentrations and effects. Samples should generally be taken at steady state and in the elimination phase to guide dosing adjustments. Request forms should document timing of sample collection, last dose, dosing regimen, patient details, and reason for monitoring. TDM helps individualize therapy, avoid toxicity, assess compliance, and detect drug interactions.

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    Concept of Therapeutic Drug Monitoring TDM

    Uploaded by

    Walaa Yousef
    104 views33 pages
    Therapeutic drug monitoring (TDM) involves measuring drug concentrations in biological fluids and interpreting those concentrations based on the drug's pharmacokinetics, dosing history, and the patient's condition. TDM is indicated for drugs with a narrow therapeutic index, significant pharmacokinetic variability between patients, and an established relationship between concentrations and effects. Samples should generally be taken at steady state and in the elimination phase to guide dosing adjustments. Request forms should document timing of sample collection, last dose, dosing regimen, patient details, and reason for monitoring. TDM helps individualize therapy, avoid toxicity, assess compliance, and detect drug interactions.

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    Concept of Therapeutic Drug Monitoring Tdm

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    Therapeutic drug monitoring (TDM) involves measuring drug concentrations in biological fluids and interpreting those concentrations based on the drug's pharmacokinetics, dosing history, and the patient's condition. TDM is indicated for drugs with a narrow therapeutic index, significant pharmacokinetic variability between patients, and an established relationship between concentrations and effects. Samples should generally be taken at steady state and in the elimination phase to guide dosing adjustments. Request forms should document timing of sample collection, last dose, dosing regimen, patient details, and reason for monitoring. TDM helps individualize therapy, avoid toxicity, assess compliance, and detect drug interactions.

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    © All Rights Reserved
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    Download as pdf or txt
    104 views33 pages

    Concept of Therapeutic Drug Monitoring TDM

    Uploaded by

    Walaa Yousef
    Therapeutic drug monitoring (TDM) involves measuring drug concentrations in biological fluids and interpreting those concentrations based on the drug's pharmacokinetics, dosing history, and the patient's condition. TDM is indicated for drugs with a narrow therapeutic index, significant pharmacokinetic variability between patients, and an established relationship between concentrations and effects. Samples should generally be taken at steady state and in the elimination phase to guide dosing adjustments. Request forms should document timing of sample collection, last dose, dosing regimen, patient details, and reason for monitoring. TDM helps individualize therapy, avoid toxicity, assess compliance, and detect drug interactions.

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    of 33

    Concept of Therapeutic drug monitoring

    Prof. Branislava Miljković


    Faculty of Pharmacy, University of Belgrade, Serbia
    EAHP Member of Scientific Committee
    Disclosures/Conflict of Interest

    No financial, business or personal conflicts of interest to disclose


    Outline
    Basic Clinical Pharmacokinetics
    - Pharmacokinetic parameters relevant for dosage regimen

    Concept of Therapeutic drug monitoring


    - indications; which drugs; optimal sampling time; what to
    document
    Relationship
    dose – effect
    PK - PD

    plasma clinical
    dose site of action effect
    conc. outcome

    pharmacokinetics (PK) pharmacodynamics (PD)

    What the body does to the drug? What the drug does to the body?
    A – absorption
    D – distribution
    M – metabolism
    E - excretion
    Relevance of PK
    Answer to questions:

    • What dose to give?


    • How often to give it ?
    - When is steady-state achieved ?
    • How to change the dose in certain medical conditions ?
    • How some drug-drug interactions occur ?
    Basic clinical pharmacokinetics Pharmacokinetic
    parameters
    • Bioavailability (F)
    • Volume of distribution (Vd)
    • Clearance (CL)
    • Half-life (t1/2)
    ---
    • Peak conc. (Css max)
    • Trough conc (Css min)
    • Area under the curve (AUC)
    Bioavailability

    The fraction (F) of the administered dose of the drug that


    reaches the systemic circulation available to have an
    effect (0-1)

    AUCp .o .
    F=
    AUCi .v .
    Bioavailability
    Relevance:
    If F<1 (100%)
    Absorbed dose = administered dose x bioavailability
    • Calculation of p.o. dose based on F and i.v. dose
    Question:
    If drug Z has 50% bioavailability and standard i.v. dose is
    100mg, what should oral dose be?

    Answer: 100mg
    D= = 200mg
    0.5
    (apparent) Volume of distribution
    • Volume of distribution (Vd) describes the volume
    into which the drug would have to be distributed in order
    to obtain the same plasma

    Amount of absorbed drug


    Vd =
    C

    Drug with low Vd


    Drug with high Vd
    2
    1 2 1

    Hihg tissue
    binding
    Volume of distribution
    • Relevance:
    Loading Dose (LD) = a dose of drug sufficient to
    produce a plasma concentration of drug that would fall
    within the therapeutic window after only one dose over a
    very short interval.

    C x Vd
    LD =
    F

    Q: What is a loading dose of Drug Z (Vd is 15L, oral bioavailability 30%,


    target plasma conc. 5mg/l).
    A: LD= 5mg/L x 15L / 0.30 = 250 mg
    Clearance
    • Clearance (CL) is volume of plasma that is cleared of drug
    per unit time

    • CL = Ke x Vd

    • CL = CLrenal + CLhepatic + CLlung

    • Rate of elimination = CL x Concentration

    Rate of elimination (mg/h) volume D


    CL = = CL =
    concentration (mg/L) time AUC
    Clearance
    Relevance:
    • Maintenance Dose (MD) = The dose needed to
    maintain the concentration within the therapeutic
    window when given repeatedly at a constant interval
    • Dosing rate (mg/h) = D/τ
    C x CL x t
    MD =
    F
    Q: What is MD of CBZ for plasma level of 6mg/L, TID,
    p.o. CL is 6.5L/h, F is 75%.
    6mg/L x 6.5L/h x 8h
    A : MD = = 416mg
    0.75
    3 x 400 mg (2x200mg) CBZ
    Half-life
    • T1/2 - time taken for the concentration of drug in blood to
    fall by a half

    0.693 t1/2 = 0.693 x Vd


    t1/2 = CL
    Ke

    Half life (linear kinetics) does not depend on:


    - dose
    - dosage interval
    Half - life
    • Relevance:
    - Dose interval

    - Time to completely eliminate the


    drug from the body
    (5 x t1/2)

    - Time to reach steady state


    (Tss) depends on half life

    Tss = 4 -5 x t1/2
    Half–life and elimination rate constant (K)

    Relevance:
    Time to get to certain concentration (C*):
    - K ×t C0 æ C0 ö
    C* = C 0 × e - K ×t
    e = K × t = lnç ÷
    C* è C *ø
    C0
    ln
    t = C* C
    K o
    n
    c.
    Half–life and elimination rate constant (K)

    • Relevance:

    •Patient has a potentially toxic digoxin level of 4.4μg/L. Given that the
    half life of digoxin in this patient is 60h, for how long should digoxin
    be stopped to allow the level to fall to 1.5 μg/L.

    4.4 µg/L
    0.693 ln
    K= = 0.01155 1/h 1.5 µg/L
    60 h t= = 93h
    0.01155 1/h
    Half–life and elimination rate constant (K)

    • Relevance:
    •Determine a suitable i.v. bolus dose for drug A that follows liner, one-
    compartment pharmacokinetics (half life is 4h, Vd 5L) to maintain plasma
    conc. above 4mg/L for 12h.

    - K ×t
    C* = C 0 × e 4mg / L = C 0 × e -0.17 x12

    -2.04
    4mg / L = C 0 × e C 0 = 30.8 mg/L

    D = C x Vd = 30.8 mg/L x 5 L = 154 mg


    PK steady state (ss)

    Peak conc. (Css max)


    Average conc. (Css avg)
    Trough conc.(Css min)

    Dosing interval (τ)

    Rate in =Rate out


    Contributing factors to dosing

    Vd CL Absorption

    t1/2 F

    How often? How much?

    + age, gender, liver and kidney function, weight, other concurrent


    diseses, the other medicines…
    Altering dose regimen
    - We can not control: CL, Vd, F

    Change in F will alter Css avg (not Peak:Trough)


    Change in Vd will alter Peak:Trough (not Cssavg)
    Change in CL will alter both Peak:Trough and Cssavg

    If disease, age, renal/hepatic function, the other drugs..


    change CL, F, V
    - We can control Dose rate (D/τ)
    Therapeutic drug monitoring (TDM)
    Therapeutic drug monitoring (TDM)
    • TDM involves the measurement of
    drug concentrations in biological
    fluid and the interpretation of those therapeutic drug
    concentrations. measurement

    • TDM is the clinical assessment of a


    drug's pharmacokinetic properties.
    + interpretation
    • Interpretation requires knowledge
    of the pharmacokinetics, sampling
    time, drug history and the patient's
    clinical condition. therapeutic drug
    monitoring
    Indications for TDM ('why do it')
    - Individualizing therapy (assesment of MD, τ ; adjustment of D)

    - Toxicity
    – diagnosing toxicity when the manifestation of toxicity and disease state are
    similar (theophylline)
    – avoiding toxicity (aminoglycosides)
    - Assessing compliance

    - Diagnosing failed therapy (TDM can help distinguish between ineffective drug
    treatment and non-compliance)

    - Change in patient’s clinical state

    - Monitoring and detecting drug interactions

    - Guiding withdrawal of therapy


    Which drugs?
    • narrow therapeutic
    index (NTI) drugs

    • significant pharmacokinetic variability


    • a reasonable relationship between plasma conc. and clinical effects

    • established target concentration range

    • availability of cost-effective drug assay.


    Timing of the plasma sample('when to do it')
    In most cases when SS is reached
    - earlier if toxicity is suspected.
    At the appropriate time in relation to the last dose
    - generally measured in the elimination phase (correlates with Ctrough);
    gives a more reliable guide to drug dosing;

    - Cpeak some antibiotics (aminoglycosides)

    - not during the distribution phase


    (not equilibrium between
    plasma and tissue conc.)
    Therapeutic drug monitoring request ('what to document')

    Details to include on the request form


    • Time sample collected
    • Time dose given
    • Dosage regimen (dose, duration, dosage form)
    • Patient demographics (age/gender)
    • Comedications
    • Relevant co-morbidities (e.g. renal/liver disease)
    • Indications for testing (e.g. toxicity, non-compliance)
    REQUEST FORM OF TDM
    Patient Name.............................Date..........Age...........Gender.......
    Wt................Ht..............Ward..............Ordered by...............Phone No..............
    DRUG LEVEL REQUESTED....................................................
    REASON FOR REQUEST :
    ( ) Suspected toxicity ( ) Compliance ( ) ( ) Absence of therapeutic response
    Please indicate when level is needed :( )within 24 h ( )within 1-2 h ( )others....
    WHEN THE THERAPY STARTED….. TIME AND DATE OF LAST DOSE:..... Route : IV, IM, SC, PO, others....
    Dosage form............
    Time.................... Dose.......................... Freq..................................
    THIS DRUG LEVEL IS FOR :
    SAMPLING TIME : ( ) Trough or predose level Date................Time...............
    ( ) Peak level Date.............. Time..............
    DOES THE PATIENT HAVE ORGAN-SYSTEM DAMAGE ?
    ( ) Renal ( ) Hepatic ( ) Cardiac ( ) GI ( ) Endocrine ( ) Others........................….
    OTHER DRUG(S) PATIENT IS TAKING:..........................................................
    DRUG LEVEL & USUAL THERAPEUTIC RANGE...........................................
    Technologist/Chemist.................................
    INTERPRETATION...............................................................................................................................................…....
    ....................................................…….
    Pharmacists/Pharmacokinetics/Pharmacologist
    Date.......................... Time............................………
    Interpretation
    Potential for error
    • Assuming patient is at steady-state
    • Assuming patient is adherent to the therapy

    • Not knowing the sampling time in


    relation to dose administration
    • Not considering decreased renal/hepatic function
    • Not considering drug interactions
    • Using reference range as absolute values
    Interpretation
    sample concentration
    Lower than anticipated Higher than anticipated
    • Patient noncompliance • Patient noncompliance
    • Error in dosage regimen • Error in dosage regimen
    • Rapid elimination • Slow elimination
    • Poor bioavailability • Decreased renal/hepatic
    function
    • Drug-drug interaction (ind.)
    • Drug–drug interaction (inh.)
    • not achieved SS
    • Time sampling
    Interpretation
    • Before making dose adjustments, consider:
    - if the sample was taken at the correct time with respect
    to the last dose,
    - if a steady state has been reached
    - If the patient is adhered to the treatment
    - If there is a drug-drug interaction
    - If there is a liver/kidney dysfunction

    + the individual patient without rigid adherence to a target


    range.
    Methods available to individualize drug therapy

    • Clinical pharmacokinetic principles using simple


    mathematical relationships that hold for all drugs that
    obey linear pharmacokinetics
    Css * lnCss - lnCss *
    D* = xD t=
    Css K
    • Bayesian calculations represent the gold standard TDM
    approach

    • (complex) computer programs that could cover more


    drugs.
    Conclusion
    Knowledge and understanding of basic principles of Clinical
    pharmacokinetics are necessary for interpretation of
    measured concentration and individualization of drug dose.

    Measurement of serum drug conc. without appropriate


    interpretation is useless (or even misleading).

    TDM is complementary to and not a substitute for clinical


    judgement so it is important to treat the individual patient
    and not the laboratory value.

    Successful TDM service requires a coordinated effort among


    physicians, clinical pharmacists, and laboratory personnel.
    THANK YOU
    [email protected]

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