The edition · Clinical Pharmacology
Fluoxetine exposure roughly doubled in older adults on long-term dosing, and steady state took longer to reach
A PBPK model checked against drug levels argues for slower titration in the elderly. Also: children under 25 kg are underexposed to ethambutol at WHO doses, fluconazole cut tacrolimus clearance by a third after liver transplant, an algorithm that flags prescribing cascades, and an FDA supplement for Zepbound.
The edition in brief
A physiologically based pharmacokinetic model of fluoxetine, checked against drug levels in 47 Korean patients, predicted about two-fold higher fluoxetine and 1.5-fold higher total active moiety exposure in adults over 65 after prolonged 20 mg daily dosing, with delayed steady state; observed dose-normalised troughs were higher in older patients, and CYP2D6 phenotype changed total active exposure only modestly. An individual patient data analysis of 220 children on first-line TB therapy found those under 25 kg had median ethambutol exposures below the adult target at WHO doses, and model-based weight bands would raise the dose in about 40% of children. In 114 liver transplant recipients, combined donor and recipient CYP3A5 genotype determined tacrolimus clearance stepwise, and fluconazole cut clearance by 33%, requiring about 1.5-3.0 mg rather than 2.5-7.0 mg twelve-hourly. A text-mining algorithm built on Italian product information identified known prescribing-cascade drug pairs with 85.5% sensitivity and 99% specificity. The FDA recorded a supplement to Eli Lilly's tirzepatide (Zepbound) application; its content is not stated.
Paediatric TB: children under 25 kg were underexposed to ethambutol at WHO doses
Dose ethambutol precisely by current weight and reweigh during treatment; children under 25 kg are likely underexposed at WHO doses, and revised bands may follow.
Tacrolimus after liver transplant: fluconazole cut clearance by a third; donor and recipient CYP3A5 both mattered
When adding fluconazole to tacrolimus after liver transplant, pre-emptively reduce the dose and check levels early.
An algorithm flagged prescribing cascades from product information with 85% sensitivity
At each medication review, ask whether any drug was started to treat a side effect of another, and stop the cause where possible.
FDA: supplement recorded for Eli Lilly's tirzepatide (Zepbound)
An FDA supplement to Zepbound's application has been recorded; wait for the revised label before changing practice.
Long half-life drugs: wait before judging a dose change
Wait four to five half-lives — weeks, for fluoxetine — before judging a dose, especially in older adults.
Older adults on fluoxetine: expect about twice the exposure, and titrate slowly
In older adults, start fluoxetine low and titrate slowly; exposure was about twice that of younger adults and took longer to plateau.
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