Combination Screening Case Study: CytoSolve®-Enabled Evaluation of Multi-Ingredient Dietary Supplement Risk for the United States Pharmacopeial Convention (USP) Dietary Supplements Safety Modeling Expert Panel

United States Pharmacopeial Convention
The United States Pharmacopeial Convention (USP) Dietary Supplements Safety Modeling Expert Panel is a multidisciplinary body responsible for advancing science-based methods to evaluate the safety of dietary supplement ingredients and their combinations. The panel develops and assesses innovative frameworks to support public health decision-making where traditional data are limited.

Challenge

Dietary supplements frequently contain multiple ingredients, and adverse effects may arise from ingredient–ingredient interactions rather than from single components alone. For regulators and standards bodies such as USP, the key challenge is combination screening: identifying which ingredient combinations present higher potential safety concerns when direct clinical evidence is sparse or incomplete.

Traditional safety assessment methods focus largely on single ingredients and struggle to scale across dozens of possible combinations. USP required a systematic, science-grounded approach to screen and rank multi-ingredient dietary supplement (MIDS) combinations, particularly for cardiovascular risk, without relying exclusively on long-term clinical or toxicological studies.

How CytoSolve Helped

CytoSolve® contributed a mechanistic combination-screening capability to the Multi-Criteria Decision Analysis (MCDA) framework described in the published USP-led study. Within this framework, CytoSolve® specifically supported the biologic plausibility measure by providing mechanistic insight into how ingredient combinations interact at the molecular pathway level.

For selected ingredient pairs—most notably L-arginine and caffeine—CytoSolve® supplied mechanistic modeling of their combined effects on the nitric oxide (NO) production pathway, a critical regulator of cardiovascular function. Rather than evaluating ingredients independently, CytoSolve® treated each ingredient combination as a distinct biological entity, allowing the Expert Panel to assess whether the interaction of ingredients could plausibly amplify or alter physiological responses.

The outputs of CytoSolve®’s combination modeling were translated into screening categories based on predicted changes in NO production rate (e.g., 0–20%, 20–40%, ≥40% reduction). These predictions were not used as standalone safety conclusions, but as comparative screening signals integrated alongside exposure data, adverse event frequency, and severity metrics within the MCDA framework. In this way, CytoSolve® enabled USP to move beyond single-ingredient reasoning and toward combination-aware risk prioritization.

Key Benefits Realized

  • Explicit combination screening of multi-ingredient dietary supplements rather than extrapolation from single-ingredient data
  • Mechanistic differentiation between ingredient pairs based on pathway-level interaction effects
  • Ability to rank and prioritize combinations for further review using biologic plausibility signals
  • Transparent, science-linked rationale supporting Expert Panel deliberation under data uncertainty
  • Scalable screening framework applicable to dozens of hypothetical ingredient combinations

Outcome

Through the integration of CytoSolve®-enabled mechanistic modeling, the USP Dietary Supplements Safety Modeling Expert Panel was able to incorporate combination-specific biological insight into its MCDA-based screening process. The resulting framework identified specific ingredient combinations that warranted higher concern and closer scrutiny, demonstrating how in silico combination screening can strengthen regulatory and standards-setting decisions when empirical data are limited. This case study illustrates the role of CytoSolve® as an enabling technology for combination-level safety evaluation in dietary supplement oversight.