- Design
- PBPK modelling with therapeutic drug monitoring comparison
- Population
- Simulated adults 18-98; 47 Korean patients on fluoxetine 5 weeks or more
- Primary outcome
- Fluoxetine and total active moiety exposure by age and CYP2D6 phenotype
- Effect
- About 2-fold fluoxetine and 1.5-fold total active exposure in over-65s
A physiologically based pharmacokinetic (PBPK) study in CPT: Pharmacometrics & Systems Pharmacology (September 2026) simulated fluoxetine 20 mg daily in younger (18-65) and older (65-98) adults, including its active metabolite norfluoxetine and CYP2D6 phenotype, then compared predictions with therapeutic drug monitoring in 47 Korean patients on fluoxetine for at least five weeks.
In older adults, clearance was lower and steady state was reached later, giving about two-fold higher fluoxetine exposure and 1.5-fold higher total active moiety (fluoxetine plus norfluoxetine) after prolonged dosing. Observed dose-normalised trough levels were significantly higher in older patients. CYP2D6 phenotype changed parent-drug levels but total active exposure only modestly.
This is a modelling study with a small clinical check, not an outcome trial, so it does not show that older adults have more adverse effects at standard doses. But the mechanism is plausible and the direction consistent.
The practical implication: in older adults, start fluoxetine low, wait longer before increasing, and watch for late-appearing adverse effects such as hyponatraemia, falls and bleeding. Genotyping for CYP2D6 is unlikely to help.
- Start fluoxetine at a low dose in adults over 65 and wait several weeks before increasing
- Check sodium within the first weeks and again after dose changes
- Watch for falls, bleeding and agitation appearing weeks after starting
- Do not order CYP2D6 genotyping to guide fluoxetine dosing in older adults
- Plan a long washout before switching an older patient from fluoxetine to an interacting drug
Why it matters
Standard adult titration schedules may overshoot in older patients, with adverse effects appearing only after weeks.
Don't overread it
The exposure estimates are modelled and checked in 47 patients; the study did not measure adverse outcomes.
The statistics, in plain English
Two-fold higher exposure means an older adult on 20 mg may have drug levels similar to a younger adult on about 40 mg. Total active moiety includes the metabolite norfluoxetine, which is also active, so 1.5-fold is the clinically relevant figure.
Read the rest in the app
You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.
Scan to keep reading on your phone. No account needed to start.
Tomorrow morning, before your first patient
One edition a day for clinical pharmacology, written by the desk, every claim tied to its paper. Six minutes.
Get the app — free