Therapeutic Drug Monitoring Study Guide

Introduction to Therapeutic Drug Monitoring (TDM)

• TDM: Measuring drug/metabolite levels in body fluids (usually blood) to ensure medication safety and efficacy.
• Therapeutic Range: Concentration window where drug is effective (too low = ineffective; too high = toxic).

Why TDM Matters

• Lab professionals ensure correct sample timing, accurate analysis, and prompt reporting.

When TDM Is Used

• Drugs with a narrow therapeutic range.
• Drugs with variable metabolism.
• Drugs with a risk of serious side effects.

Goals of TDM

1. Ensure the right dose reaches the therapeutic range.
2. Detect interactions between multiple drugs.

Factors Affecting Drug Levels

• Age, gender, genetics, diet, co-medications, herbal products.
• TDM customizes dosing to fit each patient’s profile.

Additional Uses of TDM

• Detecting non-compliance.
• Adjusting doses due to new medications or physiological changes (kidney/liver issues).

TDM Basis

• Relies on pharmacokinetics (how the body affects the drug) and pharmacodynamics (how the drug affects the body).

Pharmacokinetics and Drug Monitoring Overview

• Pharmacokinetics: Study of how drugs move through the body over time.
• Focuses on absorption, distribution, metabolism, and elimination.
• Many factors affect these processes, making it difficult to achieve the right drug level.

Routes of Administration

1. IV: Most rapid onset (100% bioavailability).
2. IM: Large volume feasible (may be painful).
3. Oral: Most convenient; first-pass effect may be significant.
4. Rectal: Less first-pass effect; for vomiting or unconscious patient.
5. Inhalation: Often very rapid due to large surface area of the respiratory tract.
6. Transdermal: Usually very slow absorption; used for lack of first-pass effect.

• Each route affects how quickly and efficiently a drug enters the bloodstream (bioavailability).

Drug Absorption

• For orally administered drugs, absorption depends on:
  • How easily it breaks down (dissociation).
  • Its solubility in digestive fluids.
  • Its ability to pass through the intestinal lining.
• Tablets/capsules must dissolve first; liquids absorb faster.
• Most drugs move into the bloodstream by passive diffusion.
• Drugs need to be non-ionized (uncharged) and fat-soluble.
• Absorption influenced by stomach acidity, presence of food/other drugs, intestinal diseases, and age/health conditions.
• TDM helps adjust doses individually.

Drug Distribution

• Once in the blood, a drug spreads to tissues and organs.
• Fat-soluble drugs move easily into cells/tissues like fat or nerves.
• Ionized or water-loving drugs move more slowly or remain mostly in the blood.

Volume of Distribution (Vd)

• Vd: Calculation showing how much of the drug is in the blood compared to the total dose given.
• Drugs that stay mostly in the bloodstream have a small $Vd$, while those that move into tissues have a larger $Vd$.

Free vs. Bound Drugs

• Most drugs bind to proteins in the blood, like albumin.
• Only the free (unbound) portion is active.
• The free fraction can change due to illnesses (liver/kidney disease), pregnancy, malnutrition, competing drugs/substances (urea, bilirubin, hormones).

Drug Metabolism

• Drugs absorbed from the gut (except rectal ones) first go through the liver via the portal system.
• First-pass effect can reduce drug levels before they reach the bloodstream.
• The liver is the main site of drug metabolism, which varies based on genetics and liver health.
• Some drugs require conversion into active forms by liver enzymes (biotransformation).
• In patients with liver issues, metabolism slows down, increasing the risk of toxicity.
• The liver uses the mixed-function oxidase (MFO) system:
  • Phase I creates reactive intermediates.
  • Phase II makes these intermediates water-soluble for easier removal.
• Overdoses (e.g., acetaminophen) can overwhelm this system, leading to toxic buildup and liver damage.
• The MFO system can also be induced (sped up) by certain drugs or environmental factors.
• This changes drug clearance rates and half-lives, making TDM essential.
• Food (e.g., grapefruit) and substances like alcohol can interfere with drug metabolism.

Personalized Medicine and TDM

• Everyone metabolizes drugs differently.
• Genetic testing helps identify variations in drug-processing enzymes, allowing for personalized dosing plans.
• TDM is a cornerstone of personalized medicine.

Drug Elimination

• Drugs are cleared from the body through several processes.
• The free (active) portion of a drug or its metabolites are primarily eliminated by the kidneys either through glomerular filtration, renal secretion, or both.
• Some drugs, like aminoglycoside antibiotics and cyclosporine, are neither secreted nor reabsorbed by the kidney tubules.
• For these, their elimination directly depends on the glomerular filtration rate (GFR).
• If $GFR$ decreases, drug elimination slows down, increasing both the drug’s half-life and its blood concentration.

How Drugs Are Eliminated

• Most drugs follow first-order elimination, meaning they are cleared at a rate proportional to their concentration.
• This results in an exponential decrease a rapid drop when concentrations are high, and a slower drop at low concentrations, but the percentage lost per unit time remains constant.
• Drugs are eliminated by:
  • Renal excretion.
  • Liver metabolism.
  • Or a combination of both.
• Some drugs metabolized by the liver are eventually excreted in bile.
• The efficiency of elimination varies depending on how well the liver or kidneys are working.
• Helps determine safe and effective dosing.

Elimination Equation (First-Order Kinetics)

• Formula to estimate how drug concentration changes over time:
  • $CT = C₀ × e^(-kT)$
    • $C₀$ = starting concentration
    • $CT$ = concentration after time $T$
    • $k$ = elimination constant (rate of elimination)
    • $T$ = time passed
• Calculate $k$ if you know two concentrations at different times.

Example: Calculating the Elimination Constant (k)

• Gentamicin concentration at 12:00 PM = 10 µg/mL
• At 4:00 PM = 6 µg/mL
• That’s a 4-hour gap.
• Using the formula:
  • $6 = 10 × e^(-k×4)$
• Solve for $k$:
  • Divide both sides: $0.6 = e^(-4k)$
  • Take the natural log: $ln(0.6) = -4k$ → $-0.51 = -4k$
  • $k = 0.13$/hour
• Interpretation: This patient eliminates gentamicin at a rate of 13% per hour.

Predicting Drug Level Later On

• Estimate gentamicin level at midnight (8 hours after the 4 PM value of 6 µg/mL):
  • $CT = 6 × e^(-0.13×8)$
  • $CT ≈ 2.1$ µg/mL

Half-Life ($T½$)

• Time it takes for the drug’s blood level to drop by half.
  • $T½ = 0.693 / k$
• For gentamicin:
  • $T½ = 0.693 / 0.13 ≈ 5.33$ hours
• That means every 5.33 hours, the drug concentration cuts in half.

Multiple Dosing and Steady-State

• Drugs are taken in repeated doses.
• Concentrations rise (peak) after dosing and fall (trough) before the next dose.
• The goal is to keep drug levels between the therapeutic range (not too high, not too low).
• A steady rhythm (steady-state) is reached after about 5 to 7 doses, when:
  • The amount of drug going in = the amount being eliminated.
  • The peaks and troughs level out.

Pharmacodynamics: Understanding How Drugs Work

• Pharmacodynamics: Study of how drugs affect the body including both desired effects and side effects and how those effects happen.
• It focuses on the relationship between the drug concentration at its target site and the resulting biological response.

Specimen Collection in TDM

• Accurate timing is crucial.
• Trough levels: Measured just before the next dose.
• Peak levels: Usually assessed 1 hour after oral administration.
• IV aminoglycosides peak concentration is measured 90 minutes after the infusion ends.
• Adjustments are necessary based on the patient's clinical context.
• For drugs absorbed slowly, it may take hours before reaching peak levels.
• Peak levels should only be measured once a steady state is achieved.
• Serum is preferred for most drug assays, but it's important to use proper containers.
• Some drugs can bind to gel in separator tubes, leading to falsely low results.
• EDTA, citrate, and oxalate tubes are usually unsuitable due to their potential to interfere with analysis except for immunosuppressants, which are best measured in EDTA whole blood.

Pharmacogenomics

• Drug effectiveness varies among individuals due to genetic variations.
• Pharmacogenomics focuses on how genes (e.g., CYP450, CYP2D6, CYP2C9, and CYP3A4) affect drug metabolism.
• Genetic profile helps tailor drug dosing.
• Slow metabolizers: Lower doses to avoid toxicity.
• Fast metabolizers: Higher doses to maintain therapeutic levels.
• Predict potential drug interactions.
• Determine whether a drug will be effective in the first place.

Cardioactive Drugs & TDM

• Cardioactive drugs are commonly used, but only a few, like digoxin and antiarrhythmics, require routine TDM due to potential toxicity.

Digoxin

• Uses: Arrhythmias and heart failure.
• Inhibits $Na⁺/K⁺$-ATPase → increases intracellular $Ca²⁺$ → stronger heart contractions.
• Therapeutic range: 0.8–2.0 ng/mL.
• Toxicity can mimic arrhythmias and cause GI issues, visual changes, and PVCs.
• Oral absorption affected by diet, GI function, and formulation.
• About 25% is protein-bound, and it accumulates in muscle tissue.
• Elimination is mostly renal, with a 38-hour half-life.
• TDM is crucial due to its narrow therapeutic window.
• Specimens should be collected 8–10 hours after oral dose.
• Measured by immunoassays, but values may be falsely elevated in certain conditions (e.g., Digibind use, renal/hepatic failure, biotin interference).

Quinidine

• Natural antiarrhythmic derived from Cinchona bark.
• Given orally; peaks ~2 hours after dosing.
• Therapeutic range: 2–5 µg/mL, mostly protein- bound.
• Hepatic metabolism; affected by liver function and other drugs.
• Toxicity signs: nausea, PVCs, tinnitus, thrombocytopenia.
• Trough levels are typically monitored unless toxicity is suspected.

Procainamide & NAPA

• Antiarrhythmic; rapidly absorbed orally.
• Peaks in ~1 hour, 20% protein-bound.
• Eliminated by kidneys and liver; NAPA (its metabolite) is also active.
• Therapeutic ranges:
  • Procainamide: 4–10 µg/mL
  • NAPA: 12–18 µg/mL
• Toxic if total exceeds 40 µg/mL.
• Monitored by immunoassay.

Disopyramide

• Used when quinidine causes side effects.
• Oral absorption is fast and complete; peaks in 1–2 hours.
• Protein binding varies; therapeutic range: 3.0–7.5 µg/mL.
• Side effects: anticholinergic symptoms (>4.5 µg/mL), cardiac effects (>10 µg/mL).
• Eliminated mostly through renal filtration.
• TDM done using chromatography or immunoassay.

Aminoglycosides: Overview

• Antibiotics mainly used to treat gram-negative bacterial infections, with some activity against gram-positive organisms.
• Common aminoglycosides include gentamicin, tobramycin, amikacin, and kanamycin.
• They work by blocking bacterial protein synthesis but differ in their spectrum of activity.
• While effective, they come with serious risks:
  1. Ototoxicity (damage to the inner ear causing hearing or balance issues)—often irreversible.
  2. Nephrotoxicity (kidney damage affecting electrolyte balance and causing proteinuria)— usually reversible but can lead to renal failure with prolonged exposure.
• Each drug in this group has different therapeutic and toxic blood levels, so monitoring is essential.
• These drugs are not absorbed well orally and are given IV or IM only, which limits outpatient use.
• Peak serum levels are reached 1–2 hours after dosing, and they are cleared primarily through the kidneys.
• Dose adjustments are necessary for patients with reduced kidney function.
• Immunoassays are commonly used to measure blood levels.

Gentamicin

• Treats serious infections like bacteremia and septicemia, especially from Enterobacteriaceae, Pseudomonas, Acinetobacter, and S. aureus (in combo).
• Given 2–3 times daily or as once-daily high-dose (pulse) therapy in patients with good renal function.
• Therapeutic range:
  • Peak: 3.0–12.0 µg/mL
  • Trough: <2.0 µg/mL
• Main risks: nephrotoxicity and ototoxicity.
• Requires serum level monitoring and regular assessment for hearing or balance issues.
• Dose or frequency must be reduced in patients with impaired kidney function.

Tobramycin

• Used for infections from gram-negative bacilli, including Pseudomonas and Enterobacteriaceae.
• Similar risks and dosing strategy to gentamicin.
• Important to monitor:
  • Serum levels
  • Kidney function
  • Symptoms of ototoxicity
• Baseline audiology testing is often recommended.
• Therapeutic range:
  • Peak: 3.0–12.0 µg/mL
  • Trough: <2.0 µg/mL
• Trough levels above 2.0 µg/mL increase toxicity risk.

Amikacin

• Used to treat severe gram-negative bloodstream infections.
• Mechanism: Irreversibly inhibits bacterial protein synthesis.
• Can be given orally to reduce gut flora, though typically given IV or IM.
• Peak levels:
  • Reached in 30 min (IV) or 60 min (IM).
• Half-life: 2–3 hours (normal renal function).
• Accumulates in kidneys at high concentrations, increasing nephrotoxicity risk.
• Signs of toxicity:
  • Balance issues (ataxia, vertigo, dizziness)
  • Hearing loss or tinnitus
  • Kidney damage: proteinuria or elevated nitrogen levels
• Therapeutic range:
  • Peak: 20.0–35.0 µg/mL
  • Trough: <8.0 µg/mL

Vancomycin

• A glycopeptide antibiotic effective against gram- positive organisms.
• Poor oral absorption → given IV.
• Peak levels occur ~1 hour post-dose.
• 55% protein-bound, eliminated mainly via the kidneys.
• Toxicity increases above the therapeutic range (10–20 µg/mL):
  • Nephrotoxicity: common when trough >20 µg/mL
  • Ototoxicity: more likely when peak >40 µg/mL
  • Red man syndrome: flushing of the face and extremities
• Only trough levels are typically monitored due to a long distribution phase.
• Half-life: 4–6 hours.
• Blood levels are measured by immunoassay.

Antiepileptic Drugs (AEDs)

• AEDs are prescribed to manage and prevent seizures.
• They only work while active drug levels are present in the body.
• Each drug has a therapeutic range.
• First-generation AEDs typically have narrow therapeutic windows, while second-generation ones often lack clearly defined ranges.
• Therapeutic drug monitoring (TDM) plays a crucial role in treatment.
• Serum levels are typically measured using immunoassays or chromatography.
• Measuring total drug levels is enough.
• Free drug levels give more accurate insight.
• TDM usually uses trough levels, taken just before the next dose.

Primidone

• Primidone is used for controlling refractory grand mal seizures.
• It's quickly absorbed and peaks within 2 hours, with a half-life of about 8 hours.
• Only 10% is protein- bound.
• In the liver, it’s metabolized into phenobarbital and PEMA (phenylethylmalonamide).
• The target blood level for primidone is 5–12 µg/mL.
• Monitoring often includes both primidone and phenobarbital.
• Toxicity is mostly due to phenobarbital buildup.
• Primidone levels are typically assessed using enzyme immunoassays.

Phenobarbital

• Phenobarbital is a long-acting barbiturate effective against various seizures.
• It has slow but complete absorption, peaking around 10 hours post-dose.
• About 50% binds to plasma proteins.
• Its half-life ranges from 70 to 100 hours.
• It's cleared by the liver and kidneys, but dysfunction in either system slows elimination.
• Due to slow kinetics, trough levels are usually measured unless toxicity is suspected.
• Side effects include sedation, fatigue, depression, and mental slowing.
• Phenobarbital is also a strong inducer of hepatic MFO enzymes.
• The therapeutic range is 20–40 µg/mL, measured by immunoassay.

Phenytoin (and Free Phenytoin)

• Phenytoin (Dilantin) is widely used for seizure control and for short-term seizure prevention post brain injury.
• It's usually taken orally, with peak levels reached in 3–12 hours.
• It binds strongly to plasma proteins (87–97%) and can be displaced by other drugs.
• Only the free (unbound) drug is pharmacologically active.
• Protein binding may decrease in conditions like anemia or hypoalbuminemia, leading to potential toxicity even if total levels appear normal.
• Toxicity may paradoxically trigger seizures, along with side effects like hirsutism, gum overgrowth, and vitamin/folate deficiencies.
• Phenytoin has a variable half-life (6–24 hours) and undergoes hepatic metabolism.
• At therapeutic levels, it follows zero-order kinetics.
• Therapeutic range:
  • Total phenytoin: 10–20 µg/mL
  • Free phenytoin: 1–2 µg/mL
• Free phenytoin is especially important in renal failure and is also measured via immunoassay.

Valproic Acid

• Valproic acid (Depakote) is used to treat absence (petit mal) seizures.
• It's well-absorbed orally and peaks in 1–4 hours.
• It is highly protein-bound (~93%), but binding decreases in renal/liver disease or when taken with competing drugs.
• It’s metabolized by the liver, and interactions with other AEDs can either speed up or slow down its breakdown.
• Its half-life ranges from 11–17 hours.
• Its therapeutic range is 50–120 µg/mL, and levels are checked mainly to avoid toxicity.
• Because protein binding is influenced by many factors, free valproic acid levels provide a more reliable assessment of therapeutic effectiveness and risk of toxicity.

Carbamazepine (Tegretol)

• Carbamazepine is effective for treating various seizure disorders but is reserved for patients who don’t respond to other AEDs due to its potential severe side effects, such as agranulocytosis and aplastic anemia.
• It has a high degree of absorption variability, and 70–80% of circulating carbamazepine binds to plasma proteins.
• Peak levels occur 4–8 hours after oral administration, and its half-life ranges from 10–20 hours.
• The drug is primarily metabolized by the liver, so liver dysfunction can lead to accumulation.
• Carbamazepine induces hepatic metabolism, requiring regular monitoring of blood levels for dosage adjustments.
• Toxicity varies and can be dose-dependent, with serious effects like leukopenia.
• Blood tests for white blood cell count and liver function are recommended before and during treatment.
• The therapeutic range is 4–12 μg/mL, with levels above 15 μg/mL associated with toxicity, including aplastic anemia.

Ethosuximide (Zarontin)

• Ethosuximide is mainly used to control petit mal seizures.
• It is well absorbed orally, with peak concentrations occurring 2–4 hours after dosing.
• Its therapeutic range is 40–100 μg/mL.
• Toxicity at high concentrations is rare and generally self-limiting, with common side effects including nausea, dizziness, and lethargy.
• Less than 5% of the drug binds to plasma proteins.
• Ethosuximide is primarily metabolized by the liver, with around 20% excreted through the kidneys.
• Its half-life is 40–60 hours.

Felbamate (Felbatol)

• Felbamate is indicated for severe epilepsy cases, such as Lennox-Gastaut syndrome in children and refractory epilepsy in adults.
• It is almost fully absorbed, with peak blood concentrations reached 1–4 hours after oral administration.
• About 30% of the drug binds to plasma proteins, with a half-life of 14–22 hours in adults.
• Felbamate is eliminated by both renal and hepatic metabolism, and liver or kidney impairments can increase its half-life.
• Enzyme inducers like phenobarbital and carbamazepine reduce the drug’s half-life.
• TDM may be necessary due to its narrow therapeutic range (25–60 μg/mL), and it should only be done after reaching steady state.
• Known serious adverse effects include fatal aplastic anemia and hepatic failure.

Gabapentin (Neurontin)

• Gabapentin is administered orally, with a bioavailability of up to 60%, which decreases with antacid use.
• It can be used as monotherapy or in combination with other AEDs for complex partial seizures and certain types of pain.
• Peak levels are reached 2–3 hours after dosing.
• Gabapentin does not bind to plasma proteins and is not metabolized in the liver, being excreted unchanged by the kidneys with a half-life of 5–9 hours in patients with normal kidney function.
• Children require higher doses due to faster drug elimination.
• Impaired renal function increases the half-life.
• The therapeutic range is generally 12–20 μg/mL, though serum concentrations can vary.
• Adverse effects are typically mild, including fatigue, ataxia, dizziness, and weight gain.

Lamotrigine (Lamictal)

• Lamotrigine is used to treat both partial and generalized seizures.
• It is rapidly absorbed, reaching peak concentrations 3 hours after administration.
• Approximately 55% of lamotrigine is protein-bound and biologically inactive.
• It is mainly metabolized by the liver, with a half-life of 15–30 hours in monotherapy.
• The drug's elimination rate varies by age and physiological condition, with children metabolizing it faster than adults.
• Pregnancy accelerates clearance, peaking at 32 weeks.
• TDM is crucial to maintain therapeutic levels, with a typical range of 2.5–15 μg/mL.
• Toxicity may manifest as rashes, dizziness, or gastrointestinal issues.

Levetiracetam (Keppra)

• Levetiracetam is an oral AED that does not bind to plasma proteins, making it almost completely bioavailable.
• It reaches peak concentrations in about 1 hour after dosing.
• The drug is primarily excreted unchanged by the kidneys, with a half-life of 6–8 hours.
• Clearance is faster in children and pregnant women, and slower in the elderly.
• TDM is not usually necessary due to minimal pharmacokinetic variability but may be useful to monitor adherence or fluctuating levels during pregnancy.
• The therapeutic range is 12.0–35.0 μg/mL, with adverse effects including dizziness and weakness.

Oxcarbazepine (Trileptal)

• Oxcarbazepine is an oral prodrug, almost immediately metabolized to licarbazepine.
• It is used to treat partial seizures and generalized tonic-clonic seizures.
• Peak concentrations occur about 8 hours after dosing, with 40% of the drug bound to plasma proteins.
• Oxcarbazepine is metabolized in the liver and has a half-life of 8–10 hours in adults.
• Children require higher doses for optimal blood concentration.
• Renal dysfunction reduces drug clearance, necessitating dosage adjustments.
• TDM may be indicated in cases of suspected drug interactions or during pregnancy.
• Therapeutic blood concentrations range from 12–35 μg/mL.
• Side effects are similar to those of carbamazepine.

Tiagabine (Gabitril)

• Tiagabine is used for treating partial seizures.
• It is rapidly absorbed and reaches peak concentrations within 1–2 hours.
• About 96% of the drug binds to plasma proteins, and its half-life varies between 4–13 hours.
• Hepatic metabolism plays a significant role in its clearance, with liver dysfunction potentially increasing the half-life.
• TDM may be necessary due to individual variations in drug levels.
• Therapeutic concentrations range from 20–100 ng/mL, with CNS-related side effects like confusion, speech difficulties, sedation, and tingling sensations.

Topiramate (Topamax)

• Topiramate is used to treat partial and generalized seizures.
• It is almost completely bioavailable and binds to plasma proteins only 15%.
• Peak concentrations are reached within 1–4 hours.
• The drug has a half-life of 20–30 hours and is primarily eliminated by renal filtration, with some hepatic metabolism.
• Children require higher doses to achieve therapeutic plasma concentrations.
• Renal insufficiency increases blood concentrations, while enzyme-inducing AEDs may decrease its levels.
• TDM may be necessary when therapeutic effects are not achieved or to monitor drug interactions.
• CNS side effects include taste changes and a "pins and needles" sensation in the extremities.

Zonisamide (Zonegran)

• Zonisamide is used as an adjunct for partial and generalized seizures.
• It is well absorbed orally, with peak concentrations reached 4–7 hours after dosing.
• About 60% of the drug binds to plasma proteins.
• Zonisamide has a long half-life of 50–70 hours in monotherapy, which can be reduced with enzyme- inducing AEDs.
• Children require higher doses to reach therapeutic concentrations.
• Liver or kidney disease may lead to increased blood levels.
• The therapeutic range is generally 10–40 μg/mL.
• Toxicity symptoms include breathing difficulty, low blood pressure, slow heart rate, and loss of consciousness.
• TDM may be useful for establishing baseline levels or monitoring interactions and therapeutic failure.

Psychoactive Drugs

Lithium

• Uses: Treats bipolar disorder, recurrent depression, aggressive behavior, migraines, and cluster headaches.
• Pharmacokinetics: Rapid oral absorption; peak concentrations in 2-4 hours. Does not bind to proteins. Half-life: 10-35 hours. Excreted via renal filtration, with reabsorption in renal tubules.
• Therapeutic Range: 0.5–1.2 mmol/L.
• Toxicity: Serum levels >2 mmol/L cause CNS disturbances, renal impairment, and hypothyroidism. TDM aims to avoid toxicity.
• Testing: Serum concentration measured by colorimetric methods. Avoid lithium-anticoagulant test tubes.

Tricyclic Antidepressants (TCAs)

• Uses: Treat depression, insomnia, apathy, and libido loss.
• Pharmacokinetics: Oral administration; peak concentration in 2–12 hours. 85-95% protein- bound. Half-life: 17–40 hours.
• Toxicity: Toxicity occurs at levels twice the upper therapeutic limit, leading to drowsiness, constipation, blurred vision, and severe cases such as seizures.
• TDM: Important for therapeutic efficacy and avoiding toxicity. Immunoassays for screening report “total tricyclics,” while chromatographic methods evaluate both parent drugs and metabolites.

Clozapine

• Uses: Treats refractory schizophrenia.
• Pharmacokinetics: Rapid absorption, 97% protein- bound. Peak concentrations in 2 hours. Half- life: 8–16 hours.
• Therapeutic Range: Beneficial effects observed at 350-420 ng/mL.
• TDM: Used to monitor adherence and avoid seizures due to toxicity.

Olanzapine

• Uses: Treats schizophrenia, acute manic episodes, and bipolar disorder.
• Pharmacokinetics: Oral absorption; peak concentration in 5–8 hours. 93% protein-bound. Half- life: 21–54 hours.
• Therapeutic Range: 20–50 ng/mL for optimal clinical outcomes.
• TDM: Used to balance therapeutic response and adverse effects.
• Higher blood concentrations found in women and nonsmokers.
• Adverse effects: tachycardia, decreased consciousness, coma.

Immunosuppressive Drugs in Transplant Medicine

• Transplantation medicine relies on immunosuppressive drugs to prevent graft rejection.
• Therapeutic drug monitoring (TDM) is critical due to variable pharmacokinetics and narrow therapeutic windows.

Cyclosporine

• Cyclic polypeptide; prevents host-vs-graft rejection.
• Oral bioavailability: 5–50%; highly variable.
• 98% protein-bound; sequesters in cells.
• TDM uses whole blood; target trough: 100–400 ng/mL.
• Adverse: nephrotoxicity, hypertension.
• Measured via immunoassays or chromatography.

Tacrolimus

• 100× more potent than cyclosporine; similar nephrotoxicity.
• Oral absorption varies; peak in 1–3 hrs.
• 98% protein-bound; eliminated hepatically.
• Therapeutic range: 5–15 ng/mL.
• Toxicity: anemia, leukopenia, thrombocytopenia.
• Preferred method: LC-MS/MS.

Sirolimus

• Antifungal with immunosuppressive activity.
• Long half-life (62 hrs); low bioavailability.
• Co-administered with cyclosporine or tacrolimus.
• Trough targets: 4–12 μg/L (with CsA), 12–20 μg/L (without).
• Toxicity: cytopenias, hyperlipidemia, infections.

Everolimus

• Sirolimus analog with shorter half-life.
• $CYP3A4$ metabolism—susceptible to drug interactions.
• Therapeutic range: 3–8 ng/mL.
• Toxicity: nephrotoxicity, thrombocytopenia, hyperlipidemia.

Mycophenolic Acid (MPA)

• Prodrug: mycophenolate mofetil.
• Inhibits lymphocyte proliferation.
• Oral bioavailability influenced by GI physiology.
• 95% protein-bound; half-life ~17 hrs.
• Target trough: 1–3.5 μg/mL.
• Toxicity: GI symptoms; monitored via LC-MS/MS or immunoassays.

Antineoplastics & Therapeutic Drug Monitoring (TDM)

• TDM is generally limited in antineoplastics due to rapid metabolism and incorporation into cellular structures.
• Therapeutic & toxic concentrations often overlap.
• Most drugs are IV bolus; dose delivered is more relevant than serum levels.

Methotrexate (MTX)

• One of the few antineoplastics where TDM is valuable, especially in high-dose therapy with leucovorin rescue.
• Mechanism: Inhibits DNA synthesis, affects rapidly dividing neoplastic cells more than normal cells.
• Leucovorin rescue reverses MTX toxicity if timed correctly based on MTX serum levels.

MTX Monitoring Guidelines

• Toxicity risk concentrations:
  • 10 μmol/L at 24h
  • 1 μmol/L at 48h
  • 0.1 μmol/L at 72h
• TDM Use: Guides leucovorin dosing to prevent cytotoxicity.
• PK Profile:
  • Oral or IV administration
  • Peak: 1h post-dose
  • ~50% protein bound
  • Half-life: 5–9h
  • Renal excretion
  • Preferred sample: Trough serum

Bronchodilators

Theophylline

• Used for asthma and COPD, especially in patients with nocturnal symptoms or difficulty using inhalers.
• Absorption:
  • Rapid-release: Peak in 1–2 hrs
  • Modified-release: Peak in 4–8 hrs
• Protein binding: 50–65% (mainly albumin)
• Metabolism: Primarily hepatic; ~20% renal excretion
• Half-life: 3–8 hours