Evidence from forward-looking clinical investigations indicates that using pharmacogenomics (PGx) to guide therapy decisions can lower the occurrence of serious and life-threatening drug complications. The Dutch Pharmacogenetics Working Group (DPWG) designates certain drug–gene interaction (DGI) scenarios that can avert drug-associated mortality as “essential,” yet their combined clinical and economic value has not been fully quantified. This study aims to evaluate the national-level impact and cost-effectiveness of applying “essential” PGx tests to prevent deaths linked to gene–drug incompatibility. A decision-analytic approach was constructed to estimate both the number of prevented gene–drug-related deaths and the associated financial cost over 1 year in the Dutch healthcare setting. The tested strategy involved a single-gene assay—CYP2C19, DPYD, TPMT, or UGT1A1—used to tailor therapy according to DPWG recommendations for Dutch patients beginning treatment with clopidogrel, capecitabine, systemic fluorouracil, azathioprine, mercaptopurine, tioguanine, or irinotecan. Among 148,128 individuals starting one of the seven drugs in a single year, national spending on PGx testing, interpretation, and medications would rise by €21.4 million. Within this cohort, 35,762 (24.1%) would receive an altered drug or dosage. PGx-informed prescribing would reduce mortality attributable to gene–drug mismatch by 10.6% (DGI-specific span: 8.1–14.5%), ultimately avoiding 419 deaths annually (0.3% of all initiators). The estimated economic value equates to €51,000 for each gene–drug-related death prevented (DGI-specific range: €-752,000 to €633,000). National use of PGx-based prescribing for DGIs labeled “essential” could prevent death in roughly 0.3% of new users of these medications, at a cost level considered acceptable for interventions of this scale.
