What is the therapeutic plasma concentration range for doxepin and how should therapy be adjusted based on a measured level?

Doxepin Therapeutic Plasma Concentration Range

The therapeutic plasma concentration range for doxepin (parent drug plus desmethyldoxepin metabolite) is 50-150 ng/mL, though the evidence supporting this range is weak and context-dependent, particularly when doxepin is used for sedation rather than depression. 1, 2

Recommended Therapeutic Range

The AGNP-TDM Expert Group consensus guidelines provide a therapeutic range of 50-150 ng/mL (combined doxepin plus desmethyldoxepin) with a Level 3 recommendation ("Useful"), indicating this range is based on plasma concentrations at therapeutically effective doses from steady-state pharmacokinetic studies rather than robust concentration-effectiveness relationship data. 1

Important Context for Interpretation

• Lower levels may be sufficient for sedation: The guidelines explicitly state that low levels may be adequate when doxepin is used to obtain sedation rather than for antidepressant effects. 1
• The upper limit of 150 ng/mL is more critical: This represents a safety threshold to avoid toxicity, particularly in elderly patients and children. 1

Critical Evidence Limitations

The therapeutic range for doxepin is poorly established compared to other tricyclics like nortriptyline (which has a Level 1 "strongly recommended" range of 70-170 ng/mL). 1, 3

A comprehensive 2001 analysis revealed major problems with the commonly cited ranges:

• Only 9% of 217 patient samples fell within the previously suggested 150-250 ng/mL range 2
• 88% of patients had "subtherapeutic" levels by old standards, yet many were clinically responding 2
• Mean steady-state concentration was only 89±75 ng/mL at a mean dose of 143±30 mg/day 2
• No correlation was found between plasma concentrations and clinical improvement 2

Therapy Adjustment Based on Measured Levels

If Level is Below 50 ng/mL:

• First, verify compliance and absorption: Some elderly patients show undetectable doxepin levels despite assured compliance, suggesting poor bioavailability or absorption issues. 4
• Consider dose increase if patient is non-responsive and using doxepin for depression (not sedation) 1, 2
• Rule out rapid metabolism or drug interactions affecting absorption 4

If Level is 50-150 ng/mL:

• Maintain current dose if clinically effective 1, 2
• This range is appropriate for most antidepressant indications 1
• For sedation purposes, levels at the lower end of this range are often sufficient 1

If Level is Above 150 ng/mL:

• Reduce dose immediately to prevent toxicity 1
• Monitor for signs of chronic toxicity: confusion, ataxia, QRS prolongation, seizures 5
• Consider CYP2D6 and CYP2C19 genetic testing, as poor metabolizers accumulate toxic levels 5
• Check for drug-drug interactions with CYP2D6 or CYP2C19 inhibitors 5

If Level is Above 300 ng/mL:

• This represents significant toxicity risk, particularly in children where levels of 1419 ng/mL have caused seizures and confusion mimicking epilepsy 5
• Discontinue or dramatically reduce dose 5
• Monitor ECG for QRS prolongation 5

Special Populations Requiring Monitoring

Elderly Patients:

• Routine monitoring is essential due to unpredictable bioavailability 4
• Eight of 12 elderly patients on doxepin showed undetectable plasma levels despite compliance, compared to zero patients on desipramine 4
• Maximum recommended dose is lower in elderly (though specific limits not established for doxepin as they are for nortriptyline at 40 mg/day) 3

Children:

• Maximum off-label dose is 3 mg/kg 5
• Chronic toxicity can occur from supratherapeutic dosing combined with CYP2D6/CYP2C19 genetic variability 5
• Symptoms may mimic other conditions (e.g., epilepsy) 5

Measurement Considerations

• Measure both isomers separately when possible: Doxepin exists as cis- and trans-isomers with different pharmacokinetics; trans-doxepin and both isomers of desmethyldoxepin show remarkable patient-to-patient variation 6
• Obtain trough levels at steady-state (after at least 3 weeks of consistent dosing) 1
• The combined parent drug plus metabolite concentration is what matters clinically 1, 2

Common Pitfalls to Avoid

• Do not assume therapeutic failure from "low" levels alone: Many patients respond clinically at levels below traditional ranges, particularly when using doxepin for sedation 1, 2
• Do not ignore undetectable levels in elderly patients: This may indicate absorption problems rather than non-compliance 4
• Do not overlook drug interactions: CYP2D6 and CYP2C19 inhibitors can cause dangerous accumulation 5