TDM

The measurement of blood drug concentrations for the purpose of ensuring adequate and effective treatment while avoiding potential toxicity.

The therapeutic (and toxic) response to a drug is directly related to its concentration at some specific “receptor” AND The blood concentration of the drug reflects the concentration at the target receptor. We can’t sample the receptor.

A range of serum drug concentrations associated with effective therapy but w/o significant toxicity or side effects Analogous to reference interval Derived from clinical studies (drug trials)

Optimize dose and therapeutic response —Undertreatment may be dangerous Avoid toxicity —-Overtreatment may be dangerous Detect changes or variability in pharmacokinetics Monitor compliance —Is the patient taking the drug as prescribed?

What the body does to a drug

Absorption Distribution Metabolism Elimination

What the drug does to the body effects and mechanism of action

NOT, DOSE CONCENTRATION

free drug bound to receptor site

Intravenous administration • –“instantaneous” and complete – not a variable • –requires professional administration = cost Intramuscular or subcutaneous —-slower Oral

Delivery of a drug to various compartments central – blood (and interstitial fluid) = ECF peripheral – other tissues/organs Distribution is affected by: • —binding to blood proteins • —lipophilicity (high distribution by depositing in fat) • —specific binding in tissues (ie: digoxin bound up in heart and muscle/specific receptors bind tightly

Because blood levels overestimate how much drug is actually taken up by tissues. Drug levels should be drawn AFTER distribution is complete.

Albumin • –binds acid & neutral drugs • ——–phenytoin, carbamazepine, VPA α1-acid glycoprotein (AAG, orosomucoid) —binds basic drugs ——lidocaine, tricyclic antidepressants acute phase reactant (increases during acute reaction) —Drugs bound ≥90% may be appropriate for free drug measurement (don’t do often)

Hepatic Metabolism —hepatic disease may alter dosing for drugs —–cleared primarily by metabolism Renal Elimination —decreased creatinine clearance (eGFR) may alter dosing for drugs cleared by excretion

Reactions are designed to “de-toxify” the drug and/or increase its polarity for urinary excretion Reactions may also form active drug (prodrug) or a toxin Hepatic cytochrome P450 (CYP) system 18 CYP families, 43 sub-families, involved in: drugs & other (3 families: CYP1, CYP2, CYP3) genetic variability – pharmacogenetics (-omics) warfarin – VKORC1 – warfarin target CYP2C9 – warfarin metabolism

Michaelis-Menten kinetics (1st order to drug) • –metabolizing enzymes are in excess of drug concentration • –doubling dose approximately doubles drug concentration • –True for most drugs at typical therapeutic concentrations Saturation kinetics (zero order to drug) ---therapeutic concentrations overload metabolic enzymes ----inc. dose has a disproportionate increase in drug level -----phenytoin (therapeutic range ~ sat’n) ethanol (sat’n at >0.02%) – legally drunk = 0.08%

drug concentration

Half-life (T½): the time for the blood drug concentration to decrease by 50%

Peak – time at which the concentration (at the site of action) is highest • –draw after distribution phase complete • –not commonly used (Antibiotics only?)

Trough – time of the lowest concentration JBND – just before next dose appropriate draw time for most drugs

Steady-state – net equilibrium between drug intake and elimination Time to reach steady-state is solely a function of half-life Don’t draw levels before 4-5 half-lives from initiation or after change in dosing

• Drugs with narrow (low) therapeutic index • Treatment failure – distinguish compliance vs. unusual pharmacokinetics • Assess adequacy when clinical indicators evasive • –prevent seizures, don’t titrate • —prevent rejection, don’t hope to salvage • Toxicity mimics disease (digoxin, PA, phenytoin) • Toxicity cannot be tolerated • Likely PK aberrations (drug interactions, polymorphisms, hepatic or renal disease, pregnancy)

Therapeutic Index = Toxic conc. ÷ Therapeutic conc.

Immunoassay – preferred method for most • homogeneous (EMIT, CEDIA, KIMS) • –adaptable to most standard chemistry analyzers • fluorescence polarization – Roche Integra • heterogeneous – often chemiluminescent • –standard immunassay analyzers HPLC – flexible but poorly automated —Useful if no commercial assay available (manual work ie precipitation before) -mult drugs can be measures unlike immunoassay GLC – ditto, but often requires derivatization, sometimes drugs dont exist in gas form