What is the half-life of atomoxetine (Strattera) 60mg in a poor CYP2D6 (cytochrome P450 2D6) metabolizer?

Half-life of Atomoxetine in CYP2D6 Poor Metabolizers

The half-life of atomoxetine 60 mg in a poor CYP2D6 metabolizer is approximately 24 hours, which is significantly longer than the 5-hour half-life observed in extensive metabolizers. 1

Pharmacokinetic Differences in Poor Metabolizers

Poor metabolizers (PMs) of CYP2D6 show dramatic differences in atomoxetine metabolism compared to extensive metabolizers (EMs):

• Half-life:

  • Poor metabolizers: 21.6-24 hours
  • Extensive metabolizers: 5-5.2 hours 1, 2

• Plasma concentration differences:

  • 10-fold higher AUC (area under the curve) in PMs vs EMs
  • 5-fold higher peak plasma concentrations (Cmax) in PMs 1

• Systemic clearance:

  • PMs: 0.03 L/h/kg
  • EMs: 0.35 L/h/kg 2

• Bioavailability:

  • PMs: 94%
  • EMs: 63% 2

Mechanism Behind Extended Half-Life

The extended half-life in poor metabolizers is due to:

1. Reduced enzymatic activity: CYP2D6 is the primary enzyme responsible for metabolizing atomoxetine through aromatic ring-hydroxylation, forming 4-hydroxyatomoxetine 2

2. Genetic basis: Poor metabolizers have only null alleles detected for the CYP2D6 enzyme, resulting in significantly reduced metabolic capacity 3

3. Metabolism pathway: In PMs, alternative metabolic pathways (like N-demethylation via CYP2C19) become more important but are less efficient at clearing the drug 2

Clinical Implications

The extended half-life and higher plasma concentrations in poor metabolizers have important clinical implications:

• Increased risk of adverse effects: PMs are at higher risk of toxicity due to elevated blood levels 3

• Dosing considerations: The FDA recommends dosage adjustments for poor metabolizers due to the significantly altered pharmacokinetics 1

• Drug interactions: Medications that inhibit CYP2D6 (like fluoxetine and paroxetine) can cause similar increases in atomoxetine exposure as seen in genetic PMs 3, 1

• Cardiovascular effects: The FDA has issued safety labeling changes for atomoxetine, noting that CYP2D6 PM status is a condition that predisposes patients to QT prolongation and ventricular arrhythmia 3

Identification of Poor Metabolizers

Approximately 7% of Caucasians and 2% of African Americans are poor metabolizers of CYP2D6 substrates 1. Laboratory tests are available to identify CYP2D6 PMs through genetic testing 3.

Common Pitfalls and Caveats

1. Phenocopying: Even patients who are genetically extensive metabolizers can be converted to functional poor metabolizers through drug interactions. For example, fluoxetine at a long-term dose of 20 mg/day converted an average of 43% of EMs to PMs 3

2. Adverse effect profile: Despite higher plasma concentrations in PMs, some studies suggest the frequency and severity of adverse events may be similar regardless of CYP2D6 phenotype 2, though other evidence indicates PMs have higher risk of specific side effects like dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention 4

3. Monitoring requirements: Closer monitoring for side effects is warranted in poor metabolizers due to the significantly higher drug exposure

The significantly longer half-life of atomoxetine in poor CYP2D6 metabolizers has important implications for dosing, drug interactions, and side effect management in these patients.