Therapeutic Drug Monitoring


By the end of this session the reader should be able to:

  • To understand peak and trough monitoring aminoglycoside antibiotics
  • To understand why TDM is indicated for various drugs
  • To be able to recognize common symptoms of toxicity for therapeutic drugs
  • To introduce the use of pharmacogenetics in therapeutic drug monitoring


Therapeutic drug monitoring - a strategy where a patient’s dosing schedule is modified based on measurement of serum drug concentrations

Pharmacogenetics - the study of the hereditary basis for differences in a population’s drug response

Half-life - the time it takes for the plasma concentration of a drug to decrease by fifty percent

Pharmacokinetics - a description of the time course of a drug in the body, includes processes of absorption, distribution, and elimination

Pharmacodynamics - the processes of interaction of pharmacologically active substances with target sites, and the biochemical and physiological consequences leading to therapeutic or adverse effects

Mechanism of action - the biochemical or physical process occurring at the site of action to produce a pharmacological effect


The value of therapeutic drug monitoring (TDM) as an adjunct to rational drug therapy in patients with various diseases has been firmly established. The clinician who monitors a patient’s serum drug concentration is in a position to know why a patient either is not responding satisfactorily to a particular drug dosage or is experiencing side effects to a standard therapeutic dosage of a drug. Without question, TDM has significantly improved patient care. For example, more than 80% of all epileptic inpatients can have their disorder controlled with a single drug at appropriate dosages if the concentrations of that drug in plasma are routinely monitored. This contrasts sharply with previous dosage regimens for the epilepsies, which almost invariably involved administration of at least two or three drugs to produce the desired anticonvulsant effect.


  • Noncompliance can be identified
  • Individual variations in drug-disposition patterns can be dealt with appropriately
  • Altered drug utilization as a consequence of disease can be readily identified
  • Compensation for an altered physiological state (e.g., age related changes in metabolism)
  • Drug interactions, can be identified


  1. What therapeutic information can be derived from this test (e.g., compliance, altered pharmacokinetics, toxicity)?
  2. What are the concentrations for therapeutic and toxic effects?
  3. What are the clinical effects with serum concentrations higher or lower than the therapeutic range?
  4. Does the drug have a narrow therapeutic range?
  5. What is the specificity of the assay?
  6. What is the time relationship between dose and sample collection?
  7. Does the clinical value of these results justify their cost?



  • TDM necessary because drug often exhibits saturated kinetics at therapeutic doses
  • Antiepileptic, modulates synaptic sodium channels by prolonging inactivation
  • Anti-epileptic therapeutic concentrations range from 10 to 20 mg/L
  • 90-95% protein bound
  • Apparent half-life 8 to 60 hours (dose dependant)
  • Difficult to determine when steady state is reached (5 to 30 days)
  • Time for collection is dictated by reason for monitoring, monitor peak for toxicity (4-8 hours after oral dose) and trough (just before next dose) to ensure adequate therapeutic response
  • Dose adjustment is primarily empirical
  • Toxicity characterized by: nystagmus, drowsiness, ataxia, confusion, tremors, and seizures
  • Treat toxicity by limiting drug
  • A common adverse effect with chronic use is gingival hyperplasia (40-50% prevalence)


  • A methylxanthine used to treat difficult cases of asthma (a third-line therapy)
  • Inhibits cyclic nucleotide phosphodiesterase enzymes (PDE’s), leading to an increase in cAMP and cGMP and is a competitive antagonist at adenosine receptors, causing relaxation of bronchial smooth muscles
  • Causes an increase in circulating concentrations of catecholamines
  • Pharmacokinetics are age dependent (average half-life about 3.5 hours in children, 8-9 hours in adults)
  • Phenytoin and phenobarbital increase theophylline clearance two-fold
  • Primarily cleared by liver metabolism
  • Therapeutic concentrations are in the range of 10 to 20 mg/L
  • Overdose treated with activated charcoal and hemodialysis or charcoal hemoperfusion
  • Chronic intoxication more severe than acute
  • Toxicity characterized by nausea, vomiting, hypokalemia, hyperglycemia, seizures, tachycardia, anion gap, metabolic acidosis

Valproic Acid (Depakene or Depakote)

  • Inhibits GABA transaminase, therefore increasing concentrations of GABA
  • Rapidly and completely absorbed after oral administration
  • Peak concentrations occur 1-4 hours post dose
  • Half-life varies with age (16 hours in healthy adults, 8 hours in children), duration of therapy (adult chronic therapy, half-life of 12 hours), and hepatic disease
  • Therapeutic range 50-100 mg/L (trough)
  • Concentrations above 100 mg/L are associated with hepatic toxicity and acute toxic encephalopathy


  • Hyperpolarizes GABAa receptor
  • Slowly but completely absorbed (4 to hours peak concentration after oral dose)
  • Long elimination half-life (70 to 100 hours)
  • Therapeutic range 10-40 mg/L (trough)
  • Toxicity includes: sedation, ataxia, slurred speech, and CNS depression

Primidone (Mysoline)

  • Active metabolite phenobarbital contributes to pharmacological effect, need to measure parent drug and phenobarbital
  • Rapidly and completed absorbed after oral dose
  • Half-life of about 10 hours
  • Therapeutic range 5-12 mg/L (trough)
  • Toxicity includes: nausea, vomiting, dizziness, ataxia, and CNS depression

Carbamazepine (Tegretol)

  • Slowly and erratically absorbed
  • Highly protein bound (80%)
  • Elimination half-life changes with duration of therapy (initially 24 hours, reduces to 15- 20 hours with therapy)
  • Therapeutic range 8-12 mg/L (trough)
  • Active metabolite carbamazepine-10-11-epoxide accumulates in children
  • Toxicity characterized by blurred vision, nystagmus, and ataxia
  • Toxicity unrelated to dose includes hematological depression (leukopenia, thrombocytopenia and aplastic anemia)

Ethosuximide (Zarontin)

  • Readily absorbed from gastrointestinal tract
  • Half-life of 33 hours
  • Therapeutic range 40-100 mg/L
  • Toxicity characterized by gastrointestinal distress, lethargy, and dizziness

Digoxin (Lanoxin)

  • Cardiac glycoside that inhibits Na/K-ATPase
  • Variably absorbed, 25% protein bound
  • Therapeutic range 0.8-2.0 ng/mL
  • Critical that serum is drawn as a trough (at minimum 8 hours post dosing)
  • Toxicity characterized by: nausea, vomiting, green/yellow visual disturbance, premature ventricular contractions, ventricular tachycardia, and atrioventricular node block
  • Analytically difficult to measure due to multiple metabolites and cross-reactivity problems

Procainamide (Pronestyl)

  • Antiarrhythmic with active metabolite N-acetylprocainamide (NAPA)
  • Therapeutic concentration of procainamide plus NAPA 5-30 mg/L
  • Fast acetylators form more NAPA which accumulates in plasma
  • NAPA also accumulates in renal failure
  • Symptoms of intoxication include: bradycardia, prolongation of the QRS interval, AV block and arrhythmias


  • Includes: amikacin, gentamicin, tobramycin
  • Poorly absorbed orally, consequently routinely administered intravenously or intramuscularly
  • Therapeutic concentrations listed in Table 1
  • Draw peak to determine therapeutic response, trough for toxicity
  • Toxicity: ototoxic and nephrotoxic
  • Primarily renally cleared


  • Effective in suppressing host vs. graft rejection in organ transplants
  • Highly variable absorption
  • Whole blood concentration correlates well with immunosuppression and toxicity
  • Therapeutic range for renal transplant 100-300 ng/mL
  • Therapeutic range for cardiac, hepatic and pancreatic transplants 200-350 ng/mL
  • Levels exceeding therapeutic concentrations associated with renal toxicity


  • Complex lycopeptide antibiotic effective against gram positive organisms
  • Ototoxic and nephrotoxic
  • 90% of intravenous dose is excreted renally
  • Target trough concentration are 5-15 mg/L


  • Indicated for the prophylaxis of organ rejection in patients receiving renal transplants
  • Inhibits T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation
  • Sirolimus also inhibits antibody production
  • Recommended that sirolimus initially be used in combination with cyclosporine and corticosteroids
  • In patients with low to moderate immunological risk, cyclosporine should be withdrawn 2-4 months after transplantation and sirolimus dose should be increased to reach recommended blood concentrations
  • Target trough concentrations (whole blood) 4-12 ng/mL (in combination with cyclosporine) for kidney transplants
  • Excreted primarily in feces, elimination half-life of 62 hours
  • Adverse effects include: hypercholesterolemia, hypertriglyceridemia, renal dysfunction, pneumocystis carinii infection, and CMV infection


  • Indicated for the prophylaxis of organ rejection in allogeneic liver or kidney transplants
  • Recommended for use concomitantly with adrenal corticosteroids
  • Inhibits T-lymphocyte activation
  • Target trough concentration are 5-20 ng/mL (whole blood)
  • Primary route of excretion is fecal (> 90% of dose)
  • Elimination half-life of 48 hours
  • Nephrotoxic (approximately 50% of kidney transplantation patients and 40% of liver transplants)
  • Should not be used simultaneously with cyclosporine
  • Causes mild to severe hyperkalemia (10-40% of patients), therefore monitor serum potassium)
  • Causes neurotoxicity, including; tremor, headache, changes in motor function, mental status, etc.
  • Other toxicities include: hypertension, increased risk of cancer, insulin dependant diabetes mellitus


  • Genetic differences in cytochrome P450 (CYP) enzymes responsible for altered bioavailability of drugs
  • Three main CYP families responsible for most drug metabolism are CYP1, CYP2 and CYP3
  • Future directions of TDM will undoubtedly incorporate more genetic analysis of both CYP enzymes and drug transporter proteins
  • Pharmacogenomics, where a patient’s single nuclear polymorphisms (SNP’s) are tested to determine which drugs will provide the optimal response will also enhance clinical therapeutics in next several years.

Principle of patient “titration” - a caution against rigid adherence to the
therapeutic range.”


Drug t1/2 (hours) Dose Interval (hours) Therapeutic Range Critical See notes
Acetaminophen 1-3 4 10-25 mg/L > 40 mg/L
Amikacin 2.5 6-8 peak 20-30 mg/L, trough 1-8 mg/L > 40 mg/L 1
Carbamazepine 10-48 8 8-12 mg/L > 15 mg/L
Digoxin 33-51 24 trough 0.8-2.0 ng/mL > 2.5 ng/mL 2
Gentamicin 2 8 peak 4-10 mg/L, trough 1-2 mg/L > 12 mg/L 1
Lidocaine 1.8 Infusion 1.5-5 mg/L > 8.0 mg/L
Lithium 19 6-12 0.5-1.5 mmol/L > 2.0 mmol/L
NAPA 6-12 N/A 5-30 mg/L PA + NAPA > 35 mg/L 3
Phenobarbital 72-100 12 10-40 mg/L > 60 mg/L
Phenytoin 6-24 8 10-20 mg/L > 25 mg/L
Primidone 6-12 6-8 5-12 mg/L > 15 mg/L 4
Procainamide (PA) 3-5 4-6 PA 4-10 mg/L, NAPA 5-30 mg/L, PA + NAPA 5-30 mg/L PA + NAPA > 35 mg/L 3
Quinidine 4-7 6 trough 2.3-5.0 mg/L > 7 mg/L
Salicylate 2-19 4 10-30 mg/dL > 45 mg/dL
Theophylline 3-9 10-20 ug/mL > 30 ug/mL
Tobramycin 2 8 peak 4-10 mg/L, trough 0.5-1.5 mg/L > 12 mg/L, >5 mg/L 1
Valproic acid 8-15 8 50-100 mg/L > 200 mg/L
Vancomycin 5.0-6.5 6-12 peak 30-40 mg/L, trough 5-15 mg/L > 50 mg/L, > 15 mg/L 1

1. Draw trough immediately prior to next dose

  • For intramuscular dose, draw peak 45-60 minutes post dose
  • For 30 minute intravenous infusion, draw peak 30 minutes post dose
  • For 60 minutes intravenous infusion, draw peak 15 minutes post dose

2. Draw specimen > 8 hours after dosing

3. N-acetylprocainamide (NAPA) is the active metabolite of procainamide (PA); it has similar pharmacological effects as the parent compound; both should be monitored

4. Phenobarbital is the active metabolite of primidone and the dose is usually titrated to obtain therapeutic concentrations of phenobarbital


Case 1

A 71-year-old male with a history of orthotopic (transplanted in normal anatomic position) liver transplant 8 years prior had been taking cyclosporine chronically. The patient presents to the emergency department following a syncopal episode. His admission laboratory findings include:

Na 137, Cl 109, CO2 19, SUN 40, creatinine 2.3, glucose 159, Ca 9.2, albumin 3.0, ALK phos 202, total protein 6.5 g/dL, total bilirubin 1.2 mg/dL, direct bilirubin 0.3 mg/dL, AST 33 U/L, ALT 69 U/L.

  1. How do you interpret these baseline data? While in the hospital the patient was given two doses of ibuprofen for pain. Over the next several days his SUN and creatinine increased to 80 mg/dL and 4.3 mg/dL respectively. The patient became confused and displayed obvious tremors.
  2. How do you explain the increases in SUN and creatinine?
  3. What is the appropriate therapy for this patient?
  4. What would you expect to happen to the concentration of cyclosporine in this setting?
  5. Why was this patient becoming confused?
  6. Is this a typical drug interaction between these two drugs?

Case 2

A 46-year-old male with a history of chronic back pain of 7 years duration presents to the pain clinic seeking relief. His pain is 8-9 out of 10 and is somewhat relieved with vicodin (1 tablet as needed) and salsalate 750 mg TID. He suffers from constipation and complains that his pain is “burning and shooting” in nature. His internal medicine physician prescribes him 200 mg carbamazepine BID to help relieve pain. Six weeks later his carbamazepine is increased to 600 mg BID. Two weeks after his carbamazepine is increased to 600 mg BID the patient is brought to the emergency department by a friend who reported the patient was falling down and passing out while at work. The patient also complained of excessive sweating and nausea. His physical exam showed lateral nystagmus in both eyes and slight orthostasis, but was otherwise unremarkable. In the emergency department a stat serum carbamazepine concentration was 14.4 mg/L.

  1. Was this patient’s carbamazepine dosage monitored correctly?
  2. Could the patient’s symptoms (dizziness, nausea, etc.) be explained by his medications?
  3. Was this a preventable adverse reaction?
  4. Is this a common use for carbamazepine?
  5. How should this patient be treated?
  6. In addition to monitoring his carbamazepine concentration what other laboratory tests should be monitored?

Case 3

(Clin. Pharmacol. Ther. 70(4):391-394, 2001)

A 31-year-old female (weight 55 kg; height, 159 cm) was admitted following a car accident which had caused significant head trauma. Two months after the accident and ten days after starting a standard dose of oral phenytoin (100 mg tid) the patient manifested dysarthria, nystagmus, dysmetria, left hemifacial dyskinesia and alterations in mental status 3 hours after taking her phenytoin. The only other medication the patient was taking at this time was a low molecular weight heparin (nadroparin, 4000 IU per day, subcutaneously). A cerebral computed tomographic scan and electroencephalogram excluded possible late consequences of the head trauma. A stat phenytoin concentration was > 100 mg/L.

  1. How do you interpret this phenytoin concentration?
  2. How would you treat this patient?
  3. How would you explain this phenytoin concentration?
  4. What additional studies would you order to test your hypothesis?

Case 4

A 51-year-old male with seizure disorder presents with change in mental status x4 days. The patient is confused and disoriented with an unreliable history. His history is provided by his wife. Confusion and disorientation worsened 4 days ago, associated with slurred speech. The patient also experienced several falls in last couple of days along with seizures and complaints of right hip pain. His wife reports withholding his medication for the last 2 days after noticing signs and symptoms of toxicity. The patient has difficulty taking medications and has had multiple admissions for supratherapeutic and subtherapeutic phenytoin levels.

Active problem(s):
Alcohol abuse-continuous
Seizure disorder
Diabetes with neurological manifestations, type II

Labs Result Ref. Range
Serum urea nitrogen (mg/dL) 14 8-23
Albumin (g/dL) 3.6 3.2-4.6
Glucose (mg/dL) 101 70-110
Creatinine (mg/dL) 0.8 0.4-1.2
EGFR (ml/min) 108 94-140
Sodium (mMol/L) 139 135-145
Potassium (mMol/L) 4.0 3.5-5.0
Chloride (mMol/L) 104 95-106
CO2 (mMol/L) 28.0 24-31
Calcium (mg/dL) 8.7 8.4-10.2
PO4 (mg/dL) 3.8 2.5-4.5
Free T-4 (ng/dL) 0.6 0.7-1.9
TSH (uIU/mL) 4.87 0.49-4.67
Phenytoin (mg/dL) 47.3 10-20

Complete blood count showed mild macrocytic anemia.

  1. What additional labs would you order on this patient?
  2. Are these signs and symptoms consistent with the thyroid function studies?
  3. Are these signs and symptoms consistent with phenytoin toxicity?
  4. How should this patient be treated?
  5. How long will it take for his phenytoin to return to therapeutic concentration?
  6. What is the most likely cause of the macrocytic anemia?

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