Fall-risk in genetic variable cytochrome P450 enzymes and exposure to anticholinergic drugs - a pilot-analysis from the ADRED-study

CYP2D6, CYP2C19

Genotype-driven slow CYP2D6 metabolism increasing exposure to anticholinergic drugs cleared through that pathway

Anticholinergic drug use in older adults is associated with falls, with no established way to individualize that risk. This pilot analysis of the ADRED study, a cohort of adverse drug reactions recruited in emergency departments, included 659 patients aged 65 or older taking at least three drugs and with pharmacogenetic results for CYP2D6 and CYP2C19. Anticholinergic burden scores derived from medication were analyzed overall and separately for drugs metabolized via CYP2D6 (ABS2D6) and CYP2C19 (ABS2C19). ABS2D6 was significantly associated with falls in logistic regression (OR 1.57, 95% CI 1.09-2.26), and intermediate or poor CYP2D6 metabolizers had a 3.32 chance (95% CI 1.58-6.99) of presenting with a fall, versus 1.19 (95% CI 0.71-1.98) for normal and ultrarapid metabolizers. No association was found for CYP2C19 metabolizer status (1.10, 95% CI 0.59-2.04).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The contrast between CYP2D6, associated with falls, and CYP2C19, which is not, is the strongest argument here: it makes the association hard to explain by polypharmacy alone and points to an exposure mechanism. The authors themselves call the study hypothesis-generating, and emergency department recruitment selects by design for patients who have already had an adverse drug reaction. In practice this argues for looking at the CYP2D6-metabolized share of the anticholinergic burden in an older patient already known to be a slow metabolizer, without justifying systematic pre-prescription genotyping at this stage.

Analysis by Dr Thibaut Benquey