Therapeutic Drug Monitoring (TDM)

• Therapeutic drug monitoring (TDM) involves measuring drug concentrations and/or their metabolites in body fluids to optimize therapeutic benefits.
• The therapeutic range of a drug is the dose range within which the drug produces the desired effect.
• Blood concentrations outside the therapeutic range can lead to inefficacy or toxicity.
• Laboratory personnel play a critical role in TDM by ensuring proper specimen collection timing and accurate drug concentration measurements.

Chapter Objectives

• Identifying drug characteristics that make therapeutic drug monitoring essential.
• Identifying influencing factors of orally administered drug absorption.
• Identify factors that influence the rate of elimination.
• Defining drug distribution and discuss factors that influence it.
• Volume of distribution, elimination constant and drug half-life calculation.
• Correlating drug concentrations to pharmacokinetic and pharmacodynamic parameters.
• Listing specimen collection and handling requirements for therapeutic drug monitoring.
• Specifying the therapeutic category or use of each drug presented in this chapter.
• Describing potential toxic side effects/toxicity of the therapeutic drugs discussed.
• Applying knowledge of therapeutic drug monitoring to interpret laboratory results.

Pharmacokinetics

• Pharmacokinetics studies the movement of drugs in the body over time, including absorption, distribution, metabolism, and elimination.
• Several factors influence drug absorption, distribution, metabolism, and elimination.
• Optimal therapeutic benefit is achieved when a drug reaches the appropriate concentration at its site of action.
• Bioavailability refers to the fraction of an administered dose that reaches its site of action.

Routes of Administration

• Oral administration is the most common route of delivery due to being least invasive.
• Intravenous (IV) administration provides the most direct and effective delivery.
• Other methods include intramuscular (IM) injections, subcutaneous (SC) injections, inhalation via a nebulizer, transdermal patches, and rectal suppositories.
• Each administration method has unique characteristics that affect circulating drug concentrations.

Drug Absorption

• For orally administered drugs, absorption efficiency depends on dissociation from its administered form, solubility in gastrointestinal fluids, and diffusion across gastrointestinal membranes.
• Tablets and capsules require dissolution before absorption; liquid solutions are absorbed more rapidly.
• Hydrophobic drugs are efficiently absorbed in the stomach due to gastric acidity; weak bases are preferentially absorbed in the intestine where the pH is more alkaline.
• Factors like intestinal motility, pH, inflammation, and the presence of food or other drugs can alter absorption rates.
• Drug absorption rates may change due to age, pregnancy, or pathologic conditions.
• Therapeutic oral dosage regimens can be determined when using TDM.

Drug Distribution

• The free fraction of circulating drug can diffuse out of the vasculature.
• A drug's ability to leave circulation depends on its lipid solubility.
  • Highly hydrophobic drugs cross cell membranes easily.
  • Polar and nonionized drugs can also cross cell membranes but do not sequester into lipid compartments.
  • Ionized species diffuse out of the vasculature at a slow rate.
• The volume of distribution (Vd) relates the drug dose to its concentration in the specimen.

Free Versus Bound Drugs

• Most drugs in circulation bind to serum protein constituents.
• Usually, only the free (unbound) fraction can interact, resulting in a biologic response.
• Free drug fraction is also termed the active fraction.
• Changes in plasma protein content during inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, and acid-base disturbances can alter the active fraction.
• Albumin is the major transporter of drugs, and its concentration affects free versus bound status.
• Increased a1-acid glycoprotein during inflammation increases binding of specific drugs.
• The fraction of free drugs may also be influenced by other drugs/ endogenous substances.
• Free drug fraction measurement should be considered when clinical signs are inconsistent with the total drug measurement or for highly protein-bound drugs.

Drug Metabolism

• Substances absorbed enter the hepatic portal system, where circulating blood is routed through the liver before entering general circulation.
• The first-pass effect reduces drug concentration before reaching the circulatory system.
• Liver metabolism varies due to genetics, examined in pharmacogenomics.
• Patients with impaired liver function may have a reduced drug metabolizing capacity.

Drug Elimination

• Drugs can be cleared from the body through various mechanisms.
• The free fraction of a drug/metabolites are subject to glomerular filtration, renal secretion, or both.
• If not secreted/reabsorbed, the elimination rate of the free drug fraction directly relates to the glomerular filtration rate.
• Decreases in GFR raise drug half-lives and plasma concentrations.
• Decreases in plasma drug concentration most often occur as a first-order process.
• First-order elimination follows a general equation, where the rate of elimination is proportional to the drug concentration.
• The elimination is exponential, declining from high drug concentrations to low drug concentrations.

Elimination Example

• Formula C₁ = Coe-kt can be used to calculate the amount of drug present after a certain time period.
• Half-life T½ = 0.693/k refers to the time required for blood concentration to decrease by half.

Drug-drug interactions

• Can increase drug-like substrate leading to toxicity, but also increase drug levels to make toxic.

Stead State Kinetics

• After the first oral dose, absorption and distribution occur, followed by elimination.
• Before the concentration of the drug drops significantly, the second dose is given.
• The peak of the second dose is added to what remained from the first dose.
• Because elimination is first-order, the higher concentration results in a larger amount of elimination.
• The third through the seventh scheduled doses all have the same effect of increasing the blood concentration and the amount of elimination.
• By the end of the seventh dose, the amount of drug administered in a single dose is equal to the amount eliminated during the dosage period.
• After the seventh dose, a steady state is established, and the peak and trough concentrations can be evaluated.

Pharmacodynamics

• Pharmacodynamics studies the biochemical and physiological effects of drugs and their mechanisms of action.
• It describes the correlation between a drug's concentrations at its site of action and its pharmacological responses which may have a therapeutic and adverse effect.
• Common mechanisms of action are that a drug activates its receptors.
• Extent of responses is related to the concentrations of the drug; influenced by demographic factors and the receptor density at the site of action.
• Maximum effect can be achieved if a drug concentration is high enough.
• EC50 relates to the 50% effective concentration while consistent exposure to drugs may lead to a reduced response (tolerance).
  • Therapeutic Index = TC50/EC50

Specimen Collection

• Accurate timing is the most important aspect within specimen collection in TDM; typically, it refers to the amount of time from drug taken, to testing time, to time results have elapsed.
• Trough concentrations are drawn right before the next dose while peak concentrations are drawn 1 hour after an orally administered aminoglycoside (90 minutes for IV). Serum is appropriate.
• Follow the container to be used, as some drugs may absorb; calcium-binding anticoagulants or specimen tubes that EDTA, citrate, or oxalate, must be avoided.

Cardioactive Drugs

• Cardioactive drugs are the most widely used medicines.
• Many drugs have been developed to treat cardiac complications.
• Only inotropic agents and antiarrhythmics frequently involve TDM practice.

Pharmacogenomics

• The effectiveness of a drug within a population depends in part on how patients respond.
• For any medication, there are responders and nonresponders and their relationship to therapeutic effectiveness has recently been attributed to genetic polymorphisms of the patients' drug metabolism pathways.
• Pharmacogenomics is studying these variations and developing therapies given the genetic differences.
• One of the most prominent genes is cytochrome P450 (CYP450) the gene that encodes cytochrome P450 (CYP450), which is a family of enzymes within the MFO system.

Digoxin

• Digoxin (Lanoxin) is the treatment of cardiac arrythmias as well as congestive heart failure.
• Influenced by dietary factors, gastrointestinal motility, and formulation of the drug
• Functions by inhibiting membrane Na+, K+-ATPase, causing a decrease in intracellular potassium, increasing intracellular calcium in cardiac myocytes.
• The plasma concentration range is 0.8 to 2.0 ng/mL.
• Low potassium and magnesium potentiate digoxin actions.

Quinidine

• Quinidine is a natural product extract from the bark of the "fever tree."
• Commonly used to treat various cardiac arrhythmias.
• Formulations sulfate and gluconate and administered orally, gastrointestinal absorption is complete and peak blood concentrations occur 2 hours after.
• Plasma protein (70% to 80%)
• The half-life is 6 to 8 hours.

Procainamide and N-acetylprocainamide

• Antiarrhythmic drug that can also be used to treat PVCs
• Oral route is most common, peak blood about 1 hour, plasma proteins (20%)
• The most common administration method as its absorption is rapid and complete with peak.
• NAPA hepatic metabolite demonstrates equal antiarrhythmic potential

Adminoglycosides

• An antibiotic to treat gram, bacteria that inhibits bacterial protein synthesis (Nephrotoxicity and Ototoxicty)
• 1-2 hours as peak after administered
• 2-3 elimination rates.

Antibiotics

• Poorly absorbed through the gastro tract, administration is limited to intravenous infusion.
• Aminoglycosides have a half life of approximately 2 -3 hours
• Elimination by Renal filtration.

Gentamicin

• 2-3 times given per day by intravenous or intramuscular injections(between 3-12 mcg/mL)
• Reduced renal function leads to dosing amount
• The main toxicities associated with Gentamicin from Serum levels and symptoms consistent levels is important

Vancomycin

• Glycopeptide antibiotic with poor gastro absorption
• Reaches peak in1 hour
• Plasma Protein = to 55%
• Toxic effects - When concentrations exceed , includes Red man sundrome,nephrotoxicitiy, and ototoxcity.

AED

• Anti Epileptic Drugs are only effective when while drug is their body/ or even if the don't hit concentrations
• Narrow Therapeutic
• Can monitor Adherence, and reassess a modified medication Regimen

Phenytoin

• Slow and can protect brain tissue, also reduce protien, and monitor seziures
• Adverse effects, and effects, which may include seizures, ataxia, dizziness, and gastrointestinal disturbances.

Lithium

• Can prevent aggression and treat bipolar
• Peak Concentrations are reached 2-4 Hours After
• Excreted Renally with No Protein
• 0.5 - 1.2 mmol/L, Is a Large Portion of the Patient Population

Theophyline

• treats Pulmunory diseases with 50-65 bounded protien
• 10-20 may lead to lead to insomnia, Tachycardia
• May be used to optimize , TDM - when Suspected