European journal of drug metabolism and pharmacokinetics · 2026
Impact of SLCO1B1 Gene Polymorphisms on Vadadustat Pharmacokinetics.
СтатьяНаблюдательное исследованиеНазвание и аннотация: Перевод в очереди
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Yokoyama Satoshi, Shimada Michiko, Nakagawa Junichi, Ueno Kayo, Ishiyama Masahiro, Nakamura Norio, Tomita Hirofumi, Niioka Takenori
Аннотация
BACKGROUND AND OBJECTIVE: Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is transported into hepatocytes via OATP1B1, which is encoded by the SLCO1B1 gene. Although interindividual variability in vadadustat pharmacokinetics (PK) has been reported, the influence of SLCO1B1 polymorphisms and the clinical relevance of coproporphyrin-I (CP-I) as a biomarker of OATP1B1 activity on vadadustat exposure remain unclear in Japanese patients with chronic kidney disease-related anemia. This study evaluated the effects of SLCO1B1 polymorphisms on vadadustat plasma concentration in this population.
METHODS: A prospective observational study was conducted in 11 patients who received vadadustat. Plasma concentrations at 12 h post administration (C12) were measured using high-performance liquid chromatography with ultraviolet detection, and dose-adjusted concentrations (C12/D) were calculated. CP-I, an endogenous biomarker of OATP1B1 activity, was quantified simultaneously. SLCO1B1 c.388A>G and c.521T>C were genotyped, and haplotypes were assigned. Associations between SLCO1B1*15, vadadustat C12/D, and CP-I were analyzed.
RESULTS: A total of 71 samples were analyzed. C12/D was significantly higher in SLCO1B1*15 carriers than in noncarriers (median: 60.3 versus 37.6 µg/mL/g, P = 0.009). CP-I concentrations were also higher in SLCO1B1*15 carriers (median: 0.72 versus 0.36 ng/mL, P = 0.030). A significant correlation was observed between C12/D and CP-I (ρ = 0.627, P = 0.039).
CONCLUSIONS: SLCO1B1*15 significantly influenced vadadustat concentration, and CP-I was associated with vadadustat C12/D, suggesting an association with OATP1B1-related transporter function. These findings provide insights into variability in vadadustat PK and support the larger studies to clarify the clinical utility of therapeutic drug monitoring strategies that incorporate pharmacogenomic and biomarker information. Video abstract available in online supplementary file. Supplementary file2 (MP4 35720 KB).
METHODS: A prospective observational study was conducted in 11 patients who received vadadustat. Plasma concentrations at 12 h post administration (C12) were measured using high-performance liquid chromatography with ultraviolet detection, and dose-adjusted concentrations (C12/D) were calculated. CP-I, an endogenous biomarker of OATP1B1 activity, was quantified simultaneously. SLCO1B1 c.388A>G and c.521T>C were genotyped, and haplotypes were assigned. Associations between SLCO1B1*15, vadadustat C12/D, and CP-I were analyzed.
RESULTS: A total of 71 samples were analyzed. C12/D was significantly higher in SLCO1B1*15 carriers than in noncarriers (median: 60.3 versus 37.6 µg/mL/g, P = 0.009). CP-I concentrations were also higher in SLCO1B1*15 carriers (median: 0.72 versus 0.36 ng/mL, P = 0.030). A significant correlation was observed between C12/D and CP-I (ρ = 0.627, P = 0.039).
CONCLUSIONS: SLCO1B1*15 significantly influenced vadadustat concentration, and CP-I was associated with vadadustat C12/D, suggesting an association with OATP1B1-related transporter function. These findings provide insights into variability in vadadustat PK and support the larger studies to clarify the clinical utility of therapeutic drug monitoring strategies that incorporate pharmacogenomic and biomarker information. Video abstract available in online supplementary file. Supplementary file2 (MP4 35720 KB).