Abstract
This clinical trial developed a personalized dosing model for reducing prostaglandin E(2) (PGE(2)) in colonic mucosa using ω-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, ω-3):arachidonic acid (AA, ω-6) ratios as biomarkers of colonic mucosal PGE(2) concentration. Normal human volunteers were given low and high ω-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE(2) reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE(2) Mean colonic mucosal PGE(2) concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE(2) were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE(3) increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729-37. ©2017 AACR.