CRITICAL VALUES FOR THERAPEUTIC DRUG LEVELS TABLE OF CRITICAL LIMITS


The concept of critical values for drug levels was originally developed by the late Daniel M. Baer, MD, and first published in the April 1982 issue of MLO. This table lists the critical values for common therapeutic drugs updated in 2023 by Rajasri Chandra, MS, MBA.


DRUG Acetaminophen Amikacin Amiodarone Amitriptyline Busulfan (IV) Carbamazepine Cyclosporine


Digoxin Doxepin


Ethosuximide Everolimus


Flecainide Fluconazole


Flucytosine Gentamicin


Itraconazole Lamotrigine


Lidocaine Lithium


Nortriptyline Phenobarbital Phenytoin


Posaconazole Primidone


INDICATION Analgesic


Antimicrobial Antiarrhythmic


Antidepressant/ analgesic (neuropathic pain)


Anti-leukemic, Hematopoietic cell transplantation conditioning


Antiepileptic/ mood stabilizer


THERAPEUTIC RANGE


5-20 µg/mL


Peak: 15-30 µg/mL Trough: 4-8 µg/mL


0.5-2 µg/mL 125-250 ng/mL 900-1350  MOL/MIN 4-12 µg/mL Immunosuppressant 100-400 ng/mL


Inotrope, AV node blocker


Antidepressant Antiepileptic


0.5-2.0 ng/mL* 110-250 ng/mL


40-100 µg/mL


Immunosuppressant 3-8 ng/mL Antiarrhythmic Antifungal


Antifungal Antimicrobial


Hydroxyl itraconazole Antifungal Imipramine


Antidepressant Antifungal


Antiepileptic/mood stabilizer


Antiarrhythmic Mood stabilizer


Antidepressant/ analgesic (neuropathic pain)


Antiepileptic Antiepileptic Antifungal


Antiepileptic


Procainamide (PA) (metabolite: NAPA) Antiarrhythmic


Protriptyline Quinidine


Salicylate


Antidepressant Antiarrhythmic


Analgesic, antipyresis Anti-inflammatory


Sirolimus Tacrolimus


Theophylline Tobramycin Valproic acid


Vancomycin Voriconazole


0.2-1.0 µg/mL 4.0-20.0 µg/mL


25-50 µg/mL


Peak: 5-10 µg/mL Trough: <2 µg/mL


Not established >180-240 ng/mL


1-15 µg/mL 1.5-5 µg/mL


Acute: 1-1.6 mmol/L Chronic: 0.6-1.2 mmol/L


50-150 ng/mL 15-40 µg/mL 10-20 µg/mL >0.7 µg/mL


5-12 µg/mL


PA: 4-8 µg/mL NAPA: 10-20 µg/mL


50-170 ng/mL 2-5 µg/mL


20-100 µg/mL 100-200 µg/mL


Immunosuppressant 4-20 ng/mL Immunosuppressant 5-20 ng/mL


Bronchodilator Antibacterial


Antiepileptic/mood stabilizer


Antimicrobial Antifungal


10-20 µg/mL


Peak: 4-8 µg/mL Trough: <1.0 µg/mL


50-125 µg/mL


Trough concentrations: General: 5-15 µg/mL Pneumonia: 15-20 µg/mL


1.0-5.5 µg/mL


CRITICAL VALUE


>200 µg/mL *drawn 4 hours after ingestion


>10 µg/mL >2.5 µg/mL


>500 ng/mL >1500 µmol/min >20 µg/mL >500 ng/mL


>2.5 ng/mL >500 ng/mL


>200 µg/mL >15 ng/mL


>1.0 µg/mL


None established >100-200 µg/mL


Peak: >12 µg/mL Trough: >2 µg/mL


>0.5 ug/mL (localized) >1.0 ug/mL (systemic) None established


>20 µg/mL >6 µg/mL


>2.0 mmol/L >5 mmol/L potentially fatal


>500 ng/mL >60 µg/mL >20 µg/mL


COMMENTS


*Determination if a concentration is toxic is dependent upon when it is drawn in relation to the time of ingestion of the dose. Multiple serum concentrations will be needed to monitor improvement and removal of drug.


Peak: 30 minutes after end of infusion. Trough: before next dose. Conventional dosing protocol.


Trough concentration. Serum amiodarone levels >2.5 µg/mL had a positive predictive value of 76% for adverse drug events.


Trough concentration. Life threatening cardiac toxicity and/or seizures with concentration >1000 ng/mL.


Area Under the Curve (AUC) calculations based on post-infusion sampling and dosing protocols vary by institution.


Trough concentrations. Correlate serum concentration with clinical presentation.


Specific concentration goal dependent upon clinical situation. For concentrations drawn with intravenous therapy, blood should be drawn from site other than that where drug is infusing. (Cyclosporine adheres to plastic.) TDM levels are dependent on transplant type. Blood concentrations can be method (immunoassay or mass spectrometry) dependent.


Samples should be drawn >8 hours after last dose. *Concentrations >1.5 ng/mL may be associated with higher mortality.


Trough concentration. Trough concentration.


Trough concentration. Varies by transplant protocol.


Midpoint or trough concentration. Monitoring recommended when given concurrently with medications that may decrease metabolism (increase concentrations).


Limited TDM utility except in patients receiving hemodialysis. Concentration should be a peak drawn 2 hours post dose.


Peak: 1 hour after infusion. Trough: before next dose. Conventional dosing protocol.


None established Active metabolite of itraconazole. >500 ng/mL


Concentration = imipramine + desipramine (metabolite). Large PK variability. Should be measured within 5-7 after initiation of therapy.


Trough concentration. High concentrations generally associated with increased somnolence/confusion.


Concentration can be drawn at any point (from separate IV line).


Serum concentrations may increase in presence of hyponatremia. Concentration: 12 hours after dose.


Trough concentration. Trough concentration. Do not collect before steady state achieved.


Trough concentrations. Toxic >20 µg/mL (lateral nystagmus), >40 µg/mL (decreased mentation). Toxicity may occur at lower concentrations in presence of hypoalbuminemia. Consider free phenytoin.


None established Should be measured within 7 days of initiation therapy. >15 µg/mL


Metabolized to phenobarbital.


>10 µg/mL >40 µg/mL


>500 ng/mL >6 µg/mL


Vertigo, tinnitus 150-300 µg/mL Nausea, vomiting, hyper-ventilation 250-400 µg/mL Toxicity >500 µg/mL


>25 µg/mL >25 ng/mL >25 µg/mL


>12 µg/mL >2 µg/mL


>200 µg/mL >6 µg/mL


Mid-point or trough concentration. Procainamide monitoring is particularly important in patients who might be fast acetylators (60% to 70% of northern Europeans, and 50% of black and white Americans) and in patients with renal impairment. Procainamide and N-acetylprocainamide levels should always be measured on the same sample.


Trough concentration. Midpoint or trough concentration.


Serum concentration should be used in conjunction with clinical presentation to make decision on therapy. Multiple serum concentrations will be necessary to monitor improvement and removal of drug.


Trough concentration. Whole blood samples. Therapeutic levels can be lower when used in combination with other immunosuppresants. Blood concentrations can be method (immunoassay or mass spectrometry) dependent. Therapeutic levels depend on type of transplant, time post transplant, and other concomitant drug therapy.


Whole blood samples collected as trough. Therapeutic levels can be lower when used in combination with other immunosuppressants. Bias may be present between immunoassay and LC/MS methods.


Pulmonary literature suggest that concentrations 5-15 mg/L may be as efficacious with less toxicity. Trough concentration dependent upon drug formulation.


Peak: 1 hour after end of infusion. Trough: before next dose. Conventional dosing protocol.


Toxicity may occur at lower concentrations in presence of hypoalbuminemia. Consider free valproic acid. Trough concentration preferred.


Trough: >30 µg/mL Monitoring of peaks no longer recommended. Goal trough concentration dependent upon indication. Trough: before next dose.


Should be measured within 7 days of initiation therapy.


Ranges are approximate and may vary with laboratory and/or assay. Proper interpretation of therapeutic drug concentrations requires that the specimen be drawn at an appropriate time in relation to drug administration.


10 CLR 2023-2024 • MLO • www.clr-online.com


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