What are the normal therapeutic trough plasma concentrations of norfluoxetine and the combined fluoxetine plus norfluoxetine (active moiety) in adults on standard fluoxetine doses?

Normal Norfluoxetine Levels

The therapeutic trough plasma concentration range for norfluoxetine combined with fluoxetine (active moiety) is 120-300 ng/mL, though this represents a "useful" rather than strongly recommended reference range. 1

Specific Plasma Concentration Ranges

Combined Active Moiety (Fluoxetine + Norfluoxetine)

• The therapeutic reference range for the sum of fluoxetine plus norfluoxetine is 120-300 ng/mL in adults on standard doses, classified as a level 3 ("useful") recommendation by therapeutic drug monitoring guidelines. 1
• In elderly patients (≥60 years) receiving 20 mg daily for 6 weeks, combined fluoxetine plus norfluoxetine concentrations averaged 209.3 ± 85.7 ng/mL, which fell within the therapeutic range without unusual adverse events. 2

Individual Component Levels at Steady State

After 30 days of 40 mg/day dosing, expected ranges are:

• Fluoxetine: 91-302 ng/mL 2
• Norfluoxetine: 72-258 ng/mL 2

In a naturalistic study of 131 adults on long-term fluoxetine (mean dose 24 mg/day), geometric mean concentrations were:

• S-fluoxetine: 186 nmol/L (approximately 56 ng/mL) 3
• R-fluoxetine: 67 nmol/L (approximately 20 ng/mL) 3
• S-norfluoxetine: 247 nmol/L (approximately 76 ng/mL) 3
• R-norfluoxetine: 118 nmol/L (approximately 36 ng/mL) 3

Critical Timing Requirements for Accurate Measurement

Samples must be obtained as trough levels immediately before the next scheduled dose—typically 24 hours after the last dose for once-daily regimens—and only after steady state is achieved. 4

Steady-State Considerations

• Steady state requires approximately 5 half-lives, which for fluoxetine/norfluoxetine means 5-7 weeks after dose initiation or any dose change due to the exceptionally long elimination half-lives. 1, 4
• Norfluoxetine has a terminal half-life of 4-16 days after chronic administration, with steady state achieved at 4-5 weeks. 2
• Sampling before steady state produces misleading results and should be avoided. 4

Interpreting Abnormal Patterns

High Fluoxetine / Low Norfluoxetine Ratio

This pattern indicates CYP2D6 poor metabolizer status and represents the highest toxicity risk, requiring immediate dose reduction and consideration of pharmacogenetic testing. 1

• CYP2D6 poor metabolizers have 3.9 to 11.5-fold higher fluoxetine levels even at standard doses. 1
• The fluoxetine-to-norfluoxetine ratio is inversely correlated with CYP2D6 activity (correlation coefficient = -0.450; P < .001). 1
• This phenotype predisposes to serious adverse events including QT prolongation, seizures, cardiac arrest, and death. 1

Both Levels Low

Suspect non-adherence or recent dosing; postpone therapeutic monitoring until ≥5 weeks of steady-state dosing. 1

Both Levels Elevated

Consistent with acute overdose; provide supportive care as fluoxetine overdose typically produces mild manifestations (tachycardia, drowsiness, tremor). 1

Factors Affecting Plasma Concentrations

Dose-Concentration Relationship

• Fluoxetine exhibits nonlinear pharmacokinetics due to saturation of metabolic pathways, meaning plasma concentrations increase disproportionately with dose escalation. 2, 5
• Norfluoxetine demonstrates linear pharmacokinetics with predictable dose-proportional increases. 2
• Significant correlation exists between prescribed daily dosage and enantiomer concentrations (r = 0.44-0.48 for fluoxetine, r = 0.32-0.36 for norfluoxetine), but variability at any given dose is considerable. 3

Genetic Polymorphism Impact

• Approximately 7% of the population are CYP2D6 poor metabolizers, achieving higher S-fluoxetine concentrations and lower S-norfluoxetine levels at steady state. 2
• Chronic fluoxetine therapy converts approximately 43% of extensive metabolizers to functional poor metabolizers through potent CYP2D6 inhibition. 1

Special Populations

• Hepatic impairment: Fluoxetine half-life increases to mean 7.6 days (vs. 2-3 days normal); norfluoxetine half-life increases to 12 days (vs. 7-9 days normal). Lower or less frequent dosing is mandatory. 2
• Renal impairment: Does not significantly affect steady-state concentrations; dose adjustment not routinely necessary. 2
• Pediatric patients (ages 6-<13): Average steady-state fluoxetine concentrations are 2-fold higher (171 ng/mL) and norfluoxetine 1.5-fold higher (195 ng/mL) than adolescents, primarily explained by weight differences. 2

Clinical Utility and Limitations

The relationship between plasma concentration and clinical response remains inconsistent for fluoxetine, with considerable variability in concentrations associated with favorable therapeutic response. 6, 3

• Concentrations above 500 μg/L (500 ng/mL) appear associated with poorer clinical response than lower concentrations, suggesting a therapeutic window. 5
• In one study of 58 depressed patients, plasma levels of individual enantiomers and active moiety did not differ significantly between responders and non-responders. 3
• Therapeutic drug monitoring is classified as "useful" (level 3) rather than strongly recommended for fluoxetine, unlike tricyclic antidepressants where concentration-effect relationships are well-established. 6, 1

Common Pitfalls to Avoid

• Drawing samples during the absorption phase (within 3-10 hours of oral dosing) yields falsely elevated and unpredictable concentrations. 4
• Sampling too soon after dose changes before 5-7 weeks of steady state produces misleading results. 1, 4
• Ignoring CYP2D6 status when interpreting high fluoxetine/low norfluoxetine ratios can lead to continued dosing at toxic levels. 1
• Failing to account for drug interactions: Fluoxetine is a potent CYP2D6 inhibitor that significantly increases levels of many concomitant medications. 1, 5