Benchmarking Large Language Models for Replication of Guideline-Based PGx Recommendations

We evaluated the ability of large language models (LLMs) to generate clinically accurate pharmacogenomic (PGx) recommendations aligned with CPIC guidelines. Using a benchmark of 599 curated gene–drug–phenotype scenarios, we compared five leading models, including GPT-4o and fine-tuned LLaMA variants, through both standard lexical metrics and a novel semantic evaluation framework (LLM Score) validated by expert review. General-purpose models frequently produced incomplete or unsafe outputs, while our domain-adapted model achieved superior performance, with an LLM Score of 0.92 and significantly faster inference speed. Results highlight the importance of fine-tuning and structured prompting over model scale alone. This work establishes a robust framework for evaluating PGx-specific LLMs and demonstrates the feasibility of safer, AI-driven personalized medicine.