Therapeutic Drug Monitoring Notes

Therapeutic Drug Monitoring (TDM)

TDM analyzes drug concentrations in serum, plasma, or whole blood to maximize therapeutic benefits and minimize toxic effects.
It is especially useful for drugs with a narrow therapeutic index.
TDM is not typically applied to all medications, but only those with a narrow therapeutic window where small changes can lead to toxicities, such as Cyclosporine.

General Use of TDM

TDM is required when dosage and effects (therapeutic or toxic) have weak correlations, making dose prediction difficult (e.g., anti-psychotic, anti-epileptic agents).
Adjustments can improve therapeutic benefits without toxicity but are unsuitable when overdosing or underdosing has severe consequences or in patients with significant renal and liver disorders.
Individualized dosage regimens may be needed in disease states, making TDM beneficial for patients with illnesses, especially renal and liver problems.

Common Indications for TDM

Serious consequences of overdosing or underdosing can occur with drugs having a narrow therapeutic window.
Poor correlation between drug dose and circulating concentration, but a strong correlation between circulating concentration and effects, indicates a need for TDM.
Changes in patient’s physiology (e.g., pregnancy, liver disease) and potential drug interactions also necessitate TDM.

Key Aspects of TDM

Requires quantitative evaluation of circulating drug concentrations to optimize patient outcomes when considered with clinical context.
Factors influencing drug concentration include the route of administration, rate of absorption, drug distribution within the body, and rate of elimination.

Routes of Administration and Rate of Absorption

Intravenous (IV) is the fastest delivery route. Other routes include intramuscular (IM), subcutaneous (SC), inhalation, transcutaneous, rectal (suppository), and oral (PO).
Absorption depends on the drug's lipid solubility (drugs must be lipid-soluble for absorption but water-soluble for elimination).
Uncharged molecules are absorbed better than charged ones.

Drug Distribution and Rate of Elimination

High volume of distribution (Vd) indicates extensive distribution in tissues; low Vd means the drug remains in the bloodstream.
Drugs to be absorbed should be lipid-soluble/hydrophobic, while those to be excreted should be water-soluble/hydrophilic.
The liver is largely responsible for metabolism, while the kidneys handle secretion and elimination.

Factors Influencing Absorption

Drug formulation (liquid vs. tablets), transport mechanisms (passive diffusion vs. active uptake), drug state (hydrophobic/nonionized drugs absorb better), and gastric pH affect absorption.
Weak acids absorb well in the stomach, while weak bases absorb better in the intestines.
First-pass metabolism in the liver reduces bioavailability for drugs absorbed from the intestine (except rectal).

Free vs. Bound Drugs

Only the free (unbound) fraction of a drug is biologically active.
Changes in serum protein levels and competition for protein-binding sites affect free drug fraction.

Drug Distribution

Free drug fractions diffuse out of blood vessels into interstitial and intracellular spaces.
Hydrophobic drugs easily cross cell membranes and enter lipid compartments.
$Vd = D / Ct$ (Vd = volume of distribution, D = injected dose, Ct = plasma concentration).

Drug Elimination

Occurs via hepatic metabolism (liver) and renal filtration (kidneys).
First-order elimination: the higher the concentration, the faster the rate of elimination.
Zero-order kinetics: constant rate of elimination regardless of concentration.

Phases of Drug Metabolism

Phase I (Functionalization Reactions): oxidation, reduction, or hydrolysis to produce reactive intermediates.
Phase II (Conjugation Reaction): conjugate functional groups to Phase I products, making them water-soluble.
CYP450 enzymes play a key role in drug metabolism.
Certain xenobiotics increase enzyme activity, leading to faster drug elimination (shorter half-life).

Drug-Drug Interactions

Competitive and Noncompetitive interactions alter drug clearance unpredictably.
Liver disease leads to slower clearance (longer half-life).
Pharmacogenetics can identify individuals with genetic variations in metabolism, enabling personalized dosage regimens.

Renal Clearance

Largely occurs through glomerular filtration and renal secretion.
Decreased glomerular filtration rate (GFR) increases serum drug half-life and concentration.

Pharmacokinetics

Mathematical modeling of drug concentration in the body, considering absorption, distribution, metabolism, and elimination (ADME).
Maximizes therapeutic effect while minimizing toxic effects.

Drug Elimination

IV bolus injection results in immediate drug presence in circulation; elimination follows first-order kinetics.
Oral administration involves simultaneous absorption, distribution, and elimination.
Steady-state drug concentration (Css) is achieved after approximately 7 doses, where drug intake equals drug elimination per dose interval.

Sample Collection

Trough concentration (Cmin) is collected immediately before the next dose; peak concentration (Cmax) is typically drawn 1 hour after oral administration.
Serum or plasma is the preferred specimen, but serum separator tubes (SSTs) can absorb certain drugs, leading to falsely low results.

Pharmacogenomics

Drug effectiveness varies among individuals due to genetic polymorphisms affecting drug metabolism pathways.
Slow metabolizers require lower doses, while fast metabolizers require higher doses.

Clinical Applications of Pharmacogenomics and Cardioactive Drugs

Predicting drug-to-drug interactions and determining drug effectiveness based on genetic profiles.
Cardiac glycosides (e.g., Digoxin) and antiarrhythmics require TDM.

Digoxin

Used for congestive heart failure (CHF); inhibits Na+/K+-ATPase, increasing cardiac contractility.
Therapeutic range: 0.8-2.0 ng/mL; toxicity at >2.0 ng/mL.
Renal filtration is the primary route of elimination; decreased GFR increases digoxin levels.
Hypokalemia & Hypomagnesemia increase sensitivity to Digoxin, raising the risk of toxicity.

Antiarrhythmic Drugs Requiring TDM

Quinidine: Used to treat cardiac arrhythmias; trough levels are preferred.
Procainamide: Used for cardiac arrhythmia treatment; monitor both Procainamide & N-Acetyl Procainamide (NAPA).
Disopyramide: Alternative to quinidine for arrhythmias; interpretation should consider clinical symptoms.

Antibiotic Therapeutic Drug Monitoring

Aminoglycosides

Include Gentamicin, Tobramycin, Amikacin, Kanamycin.
Used to treat gram-negative bacterial infections; inhibits bacterial protein synthesis.
Toxicity: nephrotoxicity (reversible) and ototoxicity (irreversible).
Trough levels monitored to avoid toxicity.

Vancomycin

Used for gram-positive infections, including MRSA; inhibits bacterial protein synthesis.
Red-Man Syndrome (erythemic flushing) is a hallmark toxicity.
Trough levels preferred (therapeutic range: 5–10 µg/mL).

Antiepileptic Drug (AED) Therapeutic Drug Monitoring

AEDs are used prophylactically for epilepsy, convulsions, and seizures; therapeutic ranges are guidelines.
Trough levels are generally preferred for monitoring; free drug levels should be measured in patients with altered protein binding.

First-Generation AEDs

Phenobarbital: Controls various seizures; monitor trough levels only.
Phenytoin (Dilantin): Seizure control, brain injury prophylaxis; monitor total levels.
Valproic Acid: Used for petit mal and absence seizures; free fraction measurement is a better indicator of toxicity.
Carbamazepine: Used for various seizure disorders; monitor liver function and WBC count.
Ethosuximide (Zarontin): Used for petit mal seizures; therapeutic drug monitoring (TDM) ensures levels remain within range.

Second-Generation AEDs

Felbamate: Used for severe epilepsy; monitor TDM properly.
Gabapentin: Used for partial seizures; monitor TDM properly, but less critical as levels remain stable.
Lamotrigine: Used for partial and generalized seizures (Grand-mal and Petit-mal); TDM is less critical, but useful for compliance monitoring.
Levetiracetam: Used for partial and generalized seizures and many more, but usefulness is affected by drug interactions, and free drug levels should be confirmed.
Oxcarbazepine: Used for partial and secondarily generalized seizures, prodrug converted to licarbazepine; TDM helps in treatment of such secondarily seizures but levels may very due to renal impairment and drug interaction.
Tiagabine: Used for partial seizures; TDM confirms clinical action.
Topiramate: Used for generalized seizures and has a side effect of tingling sensation; TDM optimizes therapy.
Zonisamide: Used for partial and generalized seizures and is safe for kidney and liver, if they present diseases; TDM ensures safer dosage.

Psychoactive Drugs

Lithium

Used for bipolar disorder; TDM purpose: Prevent toxicity (not well correlated with therapeutic effects).
Therapeutic range: 0.5–1.2 mmol/L.

Tricyclic Antidepressants (TCAs)

Used for depression, insomnia, apathy, loss of libido; TDM needed as TCAs lead to many toxic effects.

Clozapine / Olanzapine

Atypical antipsychotics; TDM is useful in treatment, more efficient if TDM is included with the other atypical antipsychotics.

Immunosuppressive Drugs

Purpose: Prevent organ transplant rejection by suppressing immune response; TDM ensures efficacy and minimizes toxicity.

Cyclosporine

Used for preventing host-versus-graft disease (HvGD) rejection in organ transplants; whole blood preferred for testing.

Tacrolimus (FK-506)

100× more potent than cyclosporine; Monitor the low levels of drugs in the body after HPLC-MS processes.

Sirolimus (Rapamycin) / Mycophenolic (MPA)

Antifungal agent with immunosuppressive activity/Active form of mycophenolate mofetil (MMF); Monitor trough levels and ensure the liver performs all metabolic cycles respectively for patient.