Abstract
INTRODUCTION: 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) is an essential cofactor for multiple enzymes, including phenylalanine hydroxylase (PAH). Exogenous BH(4), or its natural precursor sepiapterin, is utilized to treat patients with phenylketonuria (PKU), a disease caused by PAH deficiency. This study aims to investigate correlation of endogenous BH(4) concentrations with related factors, circadian rhythm, sex, race, age, and disease status. METHODS: Predose or placebo treatment blood samples were collected in eight sepiapterin clinical trials from healthy adults and patients of all ages with PKU or primary tetrahydrobiopterin deficiency (PBD) to measure plasma BH(4) concentrations. Graphic visualization, descriptive statistics, and analysis of variance were used to explore the relationship between participant characteristics and BH(4) concentrations. RESULTS: In total, 1175 BH(4) measurements from 236 participants were analyzed, revealing a circadian rhythm of BH(4) concentration. In healthy adults, BH(4) had the lowest concentrations between 7:00 and 10:59 (geometric mean 2.06 ng/mL) and the highest between 19:00 and 22:59 (2.72 ng/mL). Asian participants exhibited the highest BH(4) concentration (2.33 ng/mL), whereas comparable levels were observed in Whites and Blacks or African Americans (2.01 and 2.07 ng/mL, respectively). Endogenous BH(4) in PBD patients was <0.5 ng/mL, while it was significantly higher in PKU patients (9.63 ng/mL for those >2 years). No age-dependent BH(4) change was observed in healthy adults and participants with PKU >2 years. BH(4) concentrations were higher in healthy adult males (2.18 ng/mL) than females (1.95 ng/mL), but not distinguishable between male and female patients with PKU. CONCLUSION: Circadian rhythm and significant differences between sexes and races in BH(4) concentrations were observed in healthy adults. BH(4) concentrations do not change with age in healthy adults and PKU patients >2 years. BH(4) concentrations were relatively stable between 7:00 and 10:59, providing a window for measurements with minimal variation. The significant difference in BH(4) concentrations between patients with PBD, patients with PKU, and healthy adults could be utilized as a diagnostic tool.