Pharmacogenomic and Medicinal Chemistry Perspectives on Off-label Drug Use

Off-label drug use (OLDU) is frequent in populations insufficiently represented in clinical trials, including pediatrics, rare diseases, and psychiatry. Although it broadens therapeutic options, uncertainty regarding safety and response remains a central concern. Physical chemistry properties influence drug distribution, target promiscuity, and exposure profiles in offlabel contexts. Because the biological processes that translate these intrinsic molecular properties into pharmacokinetic and pharmacodynamic phenotypes are modulated by genetic variability, pharmacogenomics may provide a complementary strategy for anticipating interindividual differences in safety and efficacy.

This narrative review integrates pharmacogenomics (PGx) evidence from curated clinical resources (ClinPGx, CPIC, DPWG, and regulatory sources) with principles of medicinal chemistry, prioritizing mechanistic evidence linking genetic variability to drug response variability in commonly prescribed off-label therapies across selected therapeutic areas.

Across the therapeutic areas examined, several drugs with frequent off-label use were identified as having available pharmacogenetic information. A subset of these agents was further discussed, considering mechanistic considerations derived from medicinal chemistry principles.

Intrinsic molecular characteristics help explain biodistribution patterns and off-target effects observed during off-label prescribing. Gene-drug interactions involving metabolizing enzymes and transporters consistently influence drug response. Evidence specifically designed for OLDU remains limited.

The convergence of medicinal chemistry and pharmacogenomics may offer a promising framework to enhance safety and precision in off-label prescribing. Although direct evidence in these settings remains limited, the established influence of genetic variation on drug pharmacokinetics and pharmacodynamics provides a biologically plausible rationale for exploring PGx-guided approaches in OLDU.