Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers

Several disorders of amino acid (AA) metabolism are treated with a protein-restricted diet supplemented with specific AA mixtures. Delivery kinetics impacts AA absorption and plasma concentration profiles. We assessed plasma profiles after ingestion of an AA mixture engineered to prolong AA absorption with Physiomimic Technology(TM) (Test) in a randomized, single-dose, four-way crossover trial in healthy volunteers (Trial Registration: ISRCTN11016729). In a two-step hypothesis, the primary endpoints were (i) significant reduction in peak plasma concentrations (C(max)) of essential amino acids (EAAs) while (ii) maintaining EAA bioavailability (AUC(0-300 min)) compared to a free AA mixture (Reference). Secondary endpoints included effects on plasma profiles of other AA groups and effects on several metabolic markers. Thirty subjects completed the study. Both co-primary endpoints were met: C(max) for EAAs was 27% lower with the Test product compared to the Reference product (ratio, 0.726, p < 0.0001); overall plasma EAA levels from the two AA mixtures was within the pre-specified bioequivalence range (AUC(0-300min) ratio, 0.890 (95% CI: 0.865, 0.915)). These findings were supported by the results of secondary endpoints. Prolongation of AA absorption was associated with modulation of several metabolic markers. It will be important to understand whether this can improve the long-term management of disorders of AA metabolism.