Codeine Pharmacogenetics as a Proof of Concept for Pediatric Precision Medicine.

Codeine is a prodrug whose analgesic efficacy derives from a 5% to 10% metabolic conversion to the active drug morphine by the polymorphic cytochrome P450 CYP2D6 enzyme system. Among individuals, codeine metabolism varies in proportion to the number and function of gene alleles. Dosing recommendations achieve therapeutic drug exposures in the great majority of the general population, who are “extensive metabolizers” possessing the wild type phenotype of 1 to 2 fully functional alleles. But codeine fails to provide adequate analgesia in many patients with reduced CYP2D6 function; of greater concern, “ultra-rapid metabolizers” (UMs), who have >3 functional genes due to gene copying, are at risk for serious adverse events including respiratory arrest and death. UMs make up 1% to 2% of the general population but as many as 28% in certain Arab, Ethiopian, and North African populations.1