Medical Biochemistry II - Therapeutic Drug Monitoring

Definition and goal of therapeutic drug monitoring (TDM)

Measure drug levels in different specimens

maximize therapeutic effect and minimize toxicity

Indications for TDM

Monitor compliance (most common)

Evaluate lack of response

prevent toxicity

optimize dosing based on

• Pharmacokinetic changes

• pharmacogentics

• drug-drug interactions

Variability in drug response

pharmacokinetic factors: different drug concentrations at the target site (same dose)
Pharmacodynamic factors: different responses to same drug concentration

pharmacogenetic factors: genetic variations affecting drug response

Pharmacokinetics, definition, factors, acronym

Study of factors affecting circulating drug levels

factors = “Ladme”

Liberation or administration

Absorption

Distribution

Metabolism

Excretion

Route of administration

Enteral (Through GI Tract): Oral (common), rectal

Parenteral (bypass GI)

• IV: directly into circulation

• IP: abdomen

• IM: muscle

• SC/ intradermal: under skin / into skin

What does route of administration affect?

Rate of absorption (fast to slow)

IV = inhaled > IM / Oral > dermal

seconds to minutes to hours

bioavailabilty

• IV: 100%

• Oral: <100%, affected by GI tract and first pass metabolism

Factors that affect oral drug absorption

Liberation: Drug release from formulation (from tablets/capsules vs liquids)

Drug properties: Size, shape, solubility in GI fluids

Absorption: Transport across GI membranes

Smaller factors: age, pregnancy, food, other drugs, GI conditions

Mechanisms for transport across GI membranes

Passive transport (high to low conc.)

• Passive diffusion (~95%, most common)

• Increased lipophilicity = easier membrane crossing

• Non-ionized polar (pH dependent) > ionized

Facilitated diffusion

• Carrier-mediated (no ATP)

Active transport (low to high conc.)

• ATP

2-compartment model

Drug distributed between plasma and tissue after absorption

Plasma conc. does NOT equal total body drug content

Factors affecting distribution

Free (unbound) drug vs plasma protein-bound drug

Lipophilicity (chemical structure)

Plasma pH and drug pKa (ionization state)

cardiac output / tissue blood flow

Factors for only free drug, and what affects it’s levels

Able to enter tissue, interact with receptors, and produce therapeutic/toxic effects

Plasma protein conc. and drug drug competitions affect free drug levels

Factors affecting plasma binding protein levels

Increased protein levels from inflammation, malignancy, pregnancy, decreased free drug fraction: Total level may seem therapeutic but effect is reduced

Decreased protein level from liver disease and nephrotic syndrome, increased free drug fraction: standard dose could cause toxicity

Volume of distribution, definition, calculation, and affecting factors

Theoretical volume in which a drug is distributed to achieve the observed plasma conc.

Vd (L) = Dose (mg) / plasma conc. (mg/L)

Size and lipophilicity

plasma protein binding

tissue prefusion: dehydrated decreases Vd

body composition: higher body fat increases Vd

Metabolism, aka, location, function, system

Biotransformation

mainly occurs in the liver

lipid soluble drugs to water soluble metabolites for renal excretion

Uses hepatic mixed-function oxidase (MFO) system

Metabolism phase reactions

Phase 1 reactions (functionalization)

• Oxidation/reduction

• hydrolysis

• Prodrug to active drug to inactive or altered activity metabolite

Phase 2 reactions

• Add polar groups to increase water solubility = easier renal excretion

First-Pass hepatic metabolism, where it matters, what it does, and results

Drugs absorbed from GI tract (except rectum) enter portal circulation first = liver first

Liver may metabolize drug before reaching systemic circulation

decreased bioavailability

Drugs with high first pass metabolism require higher doses to achieve therapeutic effect

Factors affecting drug metabolism

Physiological

• age, gender, genetics

• enterohepatic circulation, diet

• decreased metabolism in neonates and elderly

Drug interactions

• enzyme induction increases metabolism, decreased half life, apparent tolerance

• enzyme inhibition / competition decreases metabolism, increased half life, could cause toxicity

Pathological factors

• Liver disease

• decreased hepatic flow

• decreased metabolism = decreased clearance = increased half life

Elimination, definition, factors, routes

Drug removal from body, most variable pharmacokinetic parameter

Metabolism + excretion = elimination

hepatic metabolism and renal filtration routes

Hepatic elimination (liver)

Metabolism is primary, excretion is secondary

MFO system converts lipophilic drugs

metabolites may be excreted via bile = feces (GI tract)

Renal elimination (kidney)

Excretion is primary, metabolism is minimal

Glomerular filtration (only free unbound drug is filtered)

• Decreased GFR = decreased elimination

Tubular secretion

• Active, carrier mediated transport, subject to competition, drug-drug interactions

Tubular reabsorption

• lipophilic drugs reabsorbed, slower excretion

Definition of pharmacodynamics, dose response curve

Study of drug effects on the body, correlates w/ conc

Curve evaluates drug efficacy and potency, identifies therapeutic window

Therapeutic window, aka, max and min

Therapeutic range

between minimum effective concentration and minimum toxic concentration (MEC and MTC)

varies between patients

Maintenance dose

Dose required to keep drug levels within the therapeutic range

Therapeutic window with dosage perspective

Range of drug doses that are effective without causing toxicity

Narrow therapeutic window: toxic dose ~ therapeutic dose

requires close monitoring (higher risk of toxicity)

Therapeutic index, meaning, formula, interpretation

Measure of drug safety relative to effectiveness

Formula: TI = TD50 / ED50

Large TI = wide margin of safety

Small TI = narrow margin of safety, narrow therapeutic window

Steady state drug conc., definition, when it occurs, continuous IV vs intermittent dosing

Constant plasma drug level within the therapeutic range

occurs when rate of drug input = rate of drug clearance

Continuous IV

• conc. gradually increases to steady state

• maintains constant level (no peaks/troughs)

Intermittent dosing

• Fluctuates within therapeutic window

• peak after dose, trough before next dose

Significance of half life towards steady state

Determines dosing interval

helps estimate time to reach steady state

~5 half lives = reach steady state conc.

Dosing regimens, goal, peak level and trough level interpretation

Maintain drug levels within the therapeutic range

peak level: highest conc. during a dosing cycle

• should reach max effective level but not exceed MTC

Trough level: lowest conc. before next dose

• should remain above MEC

Pharmacogenomics, definition, identifies polymorphisms in, and metabolizer classes

Study of how genetic variation affects drug response

polymorphisms in drug receptors and drug metabolizing enzymes

Metabolizer classes: poor, intermediate, extensive (normal), ultra-rapid

Extensive metabolizer (EM)

Most common genotype

two normal alleles

normal enzyme activity and drug metabolism

responds to standard drug doses

Intermediate metabolizers (IM)

One normal allele and one reduced/nonfunctional allele

reduced enzyme activity

may require lower drug doses

Poor metabolizer (PM)

Two nonfunctional/variant alleles = very low or absent enzyme activity

decreased drug metabolism

requires lower doses

higher risk of toxicity

Ultrarapid metabolizer (UM)

gene variant = increased enzyme activity or expression

rapid drug metabolism/clearance

may require higher doses

risk of treatment failure/drug resistance

Timing of sample collection

Must be collected at steady state

peak level: typically drawn ~1 hour after dose

timing varies with route absorption and distribution

delayed absorption/distribution = sample should be drawn later (early sampling may give falsely low results)

trough level: collected immediately before next dose

Common drug groups requiring TDM

a/w high risk of toxicity

Cardioactive drugs

Antibiotics

Anti-epileptics

psychoactive drugs

bronchodilators

immunosuppressants

anti-neoplastics

Digoxin, use and peak level draw time

CHF and atrial fibrillation

Peak level drawn > 8 hours after dose

Lidocaine, uses and metabolite

Antiarrhythmics and local anesthetic

major metabolite is MEGX, inactive but toxic

Procainamide, use and metabolite

Antiarrhythmics

active metabolite is NAPA = must be measured with parent drug

Aminoglycosides, use, specific one, monitor, risks

For gram negative bacteria

gentamicin

Monitor peak and trough levels to ensure efficacy and prevent toxicity

Nephrotoxicity, ototoxicity

Glycopeptide, use, specific one, monitor, risks

For gram positive bacteria

vancomycin

monitor trough levels only (larger therapeutic window)

toxicity: nephrotoxicity, ototoxicity

can cause red man syndrome (infusion related reaction)

Anti-convulsants

Treat epilepsy

toxicity risk: high levels = CNS depression = possible coma

Psychiatric drugs, purpose, examples

Bipolar disorder (lithium and valproic acid)

Antidepressants (Tricyclic, amitriptyline, imipramine): active metabolite must be measured w/ their parent compound for accurate interpretation

Bronchodilator drugs, example, metabolite, purpose, toxicity and monitor

Theophylline

caffeine metabolite

treats persistent asthma in adults, COPD, and neonatal apnea

relaxes bronchial smooth muscle = bronchodilation

seizures, cardiac arrhythmias with toxicity

Monitor theophylline and caffeine levels in infants

Immunosuppressant drugs, purpose, toxicity and sample preference

Cyclosporine, tacrolimus, sirolimus

prevent rejection of transplanted organs

May cause nephrotoxicity

drugs are sequestered in RBC, whole blood (purple top EDTA) is preferred specimen

Antineoplastics drug, uses, mechanism and toxicity

Methotrexate

Treats various cancers, psoriasis, rheumatoid arthritis

Inhibits cell division, targets rapidly dividing cells (neoplastic > normal cells)

Systemic toxicity, especially GI effects