Chronic disease management often requires use of multiple drug regimens that lead to polypharmacy challenges and suboptimal utilization of healthcare services. While the rising costs and healthcare utilization associated with polypharmacy and drug interactions have been well documented, effective tools to address these challenges remain elusive. Emerging evidence that proactive medication management, combined with pharmacogenomic testing, can lead to improved health outcomes and reduced cost burdens may help to address such gaps. In this report, we describe informatic and bioanalytic methodologies that integrate weak signals in symptoms and chief complaints with pharmacogenomic analysis of ~90 single nucleotide polymorphic variants, CYP2D6 copy number, and clinical pharmacokinetic profiles to monitor drug–gene pairs and drug–drug interactions for medications with significant pharmacogenomic profiles. The utility of the approach was validated in a virtual patient case showing detection of significant drug–gene and drug–drug interactions of clinical significance. This effort is being used to establish proof-of-concept for the creation of a regional database to track clinical outcomes in patients enrolled in a bioanalytically-informed medication management program. Our integrated informatic and bioanalytic platform can provide facile clinical decision support to inform and augment medication management in the primary care setting.