It works by taking the brake off the brain’s own histamine rather than by stimulating it from outside — and a slow CYP2D6 means the same dose delivers considerably more of it.
Pitolisant treats the excessive daytime sleepiness of narcolepsy by a different route from the stimulants: it blocks the histamine H3 receptor, which normally limits the brain’s own histamine release, so histamine signalling rises and wakefulness with it. CYP2D6 clears the drug, and a poor metaboliser reaches substantially higher concentrations on the same dose. The US prescribing information therefore caps the dose for CYP2D6 poor metabolisers at 17.8 mg once daily, against 35.6 mg for everybody else. This is a label requirement rather than a CPIC guideline: CPIC lists the pair at level A but has not published guidance for it. Dose decisions belong to the clinician managing the condition, not to a raw data file.
US prescribing information for WAKIX (pitolisant). CPIC lists the CYP2D6–pitolisant pair at level A but has not published a guideline for it.