7.1 - THERAPEUTIC DRUG MONITORING

therapeutic range, toxicity

Therapeutic Drug Monitoring

Goal:

Maintain drug concentration within _ _ for efficacy and avoid _

drug-drug interactions

Therapeutic Drug Monitoring

Goal:

Identify _-_ _ and ensure appropriate dosing

nonadherence, dosage adjustment

Therapeutic Drug Monitoring

Goal:

Detect _ or need for _ _ due to physiologic changes

narrow therapeutic ranges

Therapeutic Drug Monitoring

TDM is most often used for:

Drugs with _ _ _

significant pharmacokinetic variability

critical adverse effects

Therapeutic Drug Monitoring

TDM is most often used for:

Drugs with _ _ _ or _ _ _

Pharmacokinetics

Therapeutic Drug Monitoring

The drug movement in the body

Absorption

Distribution

Metabolism

Elimination

Therapeutic Drug Monitoring

Pharmacokinetics

Involves (4) (first to last)

Dissolution

Solubility

Membrane

Pharmacokinetics

Absorption

Depends on:

_ from dosage form

_ in GI fluids

_ permeability

Passive diffusion

Active transport

Pharmacokinetics

Absorption

Absorption mechanisms:

_ _ – most drugs

_ _ – some drugs

pH, food, other drugs, disease states

Pharmacokinetics

Absorption

Affected by (4)

age, pregnancy, motility disorders

Pharmacokinetics

Absorption

Conditions (3) can alter absorption rates

solubility, polarity

Pharmacokinetics

Distribution

Depends on drug's lipid _ and _

tissues/organs

Pharmacokinetics

Distribution

Drugs may diffuse into _/_, affecting circulating levels

free, unbound

Pharmacokinetics

Distribution

Free VS Bound Drug

Only _ (_) drug is biologically active

plasma proteins

Pharmacokinetics

Distribution

Free VS Bound Drug

Binding influenced by _ _ (e.g., albumin, α1-acid glycoprotein)

free

Pharmacokinetics

Distribution

Free VS Bound Drug

Changes in protein levels (e.g., in inflammation, liver/kidney disease) affect _ drug levels

Free fraction

Pharmacokinetics

Distribution

Free VS Bound Drug

_ _ should be measured in highly protein-bound drugs or if total levels don’t match clinical effects

liver

Pharmacokinetics

Metabolism

Mainly in the _ via the hepatic portal system

Genetics

Liver disease

Enzyme induction/inhibition

Pharmacokinetics

Metabolism

Influenced by:

_ (pharmacogenomics)

_ _ (e.g., cirrhosis)

_ _/_ (by drugs, foods like grapefruit)

First-pass effect

Pharmacokinetics

Metabolism

_ _ _: Drug is metabolized in liver before reaching circulation

Modification

Conjugation

Pharmacokinetics

Metabolism

Metabolism includes:

Phase I: _ (e.g., oxidation)

Phase II: _ (e.g., with glutathione or sulfate)

Mixed-Function Oxidase (MFO)

Pharmacokinetics

Metabolism

_-_ _ system handles the large part of metabolism

Acetaminophen

Pharmacokinetics

Metabolism

_ example: Overdose overwhelms MFO → hepatotoxicity

metabolism variability

Pharmacokinetics

Metabolism

Therefore, TDM is essential for dose optimization due to _ _

Renal

Pharmacokinetics

Elimination

Main route: _ excretion (filtration and/or secretion)

GFR

increased, plasma

Pharmacokinetics

Elimination

Drugs not reabsorbed/secreted are eliminated in proportion to _

Decreases in GFR = _ drug half-lives and elevated _ concentrations

prolonged

Aminoglycosides, cyclosporine

Pharmacokinetics

Elimination

Impaired kidney function = _ half-life and risk of toxicity

Examples: _, _

Peak concentration

Steady State and Dose Regimens

highest drug level post-dose

Trough concentration

Steady State and Dose Regimens

lowest level before next dose

Steady state

Steady State and Dose Regimens

point at which the rate of drug administration equals the rate of drug elimination, resulting in a constant average concentration of the drug in the bloodstream during a dosing regimen

steady state

Steady State and Dose Regimens

TDM therefore is often measured at the _ _

Pharmacodynamics

Describes the relationship between drug concentration at the site of action and its pharmacological effects

Drug-receptor interaction

Pharmacodynamics

Most common mechanism: _-_ _

Drug concentration (in mg/L)

Pharmacodynamics

X-axis: _ _ + unit

Pharmacological response (% of Emax)

Pharmacodynamics

Y-axis: _ _ + unit

Emax

Pharmacodynamics

_: Maximum effect the drug can produce (plateau at the top)

EC50

Pharmacodynamics

_: Concentration at which 50% of the maximum effect is achieved

increases, plateaus

Pharmacodynamics

As you increase drug concentration, the effect _, until it _ (adding more drug doesn’t increase effect)

saturated

Pharmacodynamics

It is _: All receptors eventually become occupied

Blue

Pharmacodynamics

_: 1st dose

Yellow

Pharmacodynamics

_: 2nd dose

Red

Pharmacodynamics

_: 3rd dose

different dose, potency

Pharmacodynamics

Each curve represents the drug response after a _ _ or potentially different _ or affinity of the drug

right

more

Pharmacodynamics

The curve shifts to the _ with each subsequent dose

This means it takes _ drug to reach the same effect (e.g., 50% response)

tolerance

Pharmacodynamics

It may mean _ (decreased response to a drug due to continuous exposure)

Blue

Orange

Pharmacodynamics

_: Therapeutic effect (desired action)

_: Toxic (adverse) effect

EC₅₀

TC₅₀

Pharmacodynamics

_ = effective concentration for 50% of therapeutic response

_ = toxic concentration for 50% of toxic response

Therapeutic Index

Pharmacodynamics

The ratio between the EC₅₀ and TC₅₀

(TI) = TC₅₀ / EC₅₀

Pharmacodynamics

Therapeutic Index

Formula

drug safety

Pharmacodynamics

Therapeutic Index

Indicates _ _ margin

digoxin, warfarin, insulin, phenytoin, opioids

Pharmacodynamics

Therapeutic Index

Drugs with TI LESS THAN 10 (5) require TDM

Pharmacogenomics

Explains variation in drug response due to genetic differences

Responders

non-responders

Pharmacogenomics

_ benefit from drug; _-_ do not

metabolism pathways

Pharmacogenomics

Genetic polymorphisms influence drug _ _

Cytochrome P450 (CYP450)

Pharmacogenomics

Key enzyme family: _ _ system

CYP2D6, CYP2C9, CYP3A4

Pharmacogenomics

Major gene variants affecting metabolism: (3)

Slow metabolizers

Fast metabolizers

Pharmacogenomics

Drug doses can be personalized based on CYP450 genetic profile:

_ _ → lower doses to avoid toxicity

_ _ → higher doses to maintain therapeutic levels

MFO

Pharmacogenomics

MFO VS CYP450

is a system of enzymes involved in oxidation reactions, primarily in drug metabolism, which executes oxidation in full system

CYP450

Pharmacogenomics

MFO VS CYP450

One of MFO’s components is _, which catalyzes oxidation as part of MFO

enzymatic system

Pharmacogenomics

MFO VS CYP450

Hence, MFO is the entire _ _ that includes cytochrome P450 as its catalytic core

oxidation

Pharmacogenomics

MFO VS CYP450

Remember: "Metabolized by CYP3A4“ = CYP enzyme within the MFO system that does the _

Timing

Pharmacogenomics

Specimen Collection

_ is crucial for TDM accuracy

Trough level

Peak level, oral

Pharmacogenomics

Specimen Collection

_ _: Collected just before next dose

_ _ (_ drugs): 1 hour after dose

Peak level, IV aminoglycosides

drug absorption rate, steady-state

Pharmacogenomics

Specimen Collection

_ _ (_ _): 90 minutes after infusion

Consider _ _ _ and ensure _-_ before peak evaluation

Serum

Pharmacogenomics

Specimen Collection

_ is preferred for TDM (mostly)

gel separator tubes

Pharmacogenomics

Specimen Collection

Avoid _ _ _ if drug binds to gel—can cause falsely low results

EDTA, citrate, oxalate

EDTA whole blood

Pharmacogenomics

Specimen Collection

Anticoagulants (3) are generally unacceptable due to interference and altered drug distribution

Exception: _ _ _ is preferred for immunosuppressive drugs

Immunoassay

HPLC

LC-MS/MS

Pharmacogenomics

Methods of Measurement

_: Fast and cost-effective for many drugs

_: Good for multiple drug measurements

_: Gold standard for TDM