Physiologically based pharmacokinetic modeling to predict sumatriptan pharmacokinetics across OCT1 functional groups

Sumatriptan is a 5-hydroxytryptamine 1B/1D receptor agonist for acute migraine. Reduced organic cation transporter 1 (OCT1) function is associated with increased sumatriptan exposure, but its quantitative contribution to pharmacokinetic variability remains unclear. The aim of the study is to develop a whole-body physiologically based pharmacokinetic (PBPK) model describing sumatriptan PK across OCT1 functional groups and explore an exposure-matched candidate dose. A 50-mg mixed-genotype base model was developed from three clinical studies and extrapolated to 25 and 100 mg without reestimating drug-specific parameters. OCT1 functional differences were represented by changes in the effective OCT1-mediated hepatic uptake capacity (V_max). Individuals with 0 active OCT1 alleles were compared with those with 1 or 2 active alleles. Oral doses of 20, 25, and 30 mg were explored in the 0-active-allele group using a predefined exposure-matching range of 0.80-1.25 for C_max and AUC_0-9 h. Across 50-mg studies, geometric mean fold errors were 1.25 for C_max, 1.07 for AUC_0-12 h, and 1.12 for T_max. Across 25- and 100-mg studies, predicted-to-observed ratios ranged from 0.65 to 1.50. After 50 mg, predicted C_max and AUC_0-9 h ratios for the 0-active-allele group relative to the 1-or-2-active-allele group were 1.81 and 1.82, compared with observed ratios of 1.77 and 2.20. Both 25 and 30 mg in the 0-active-allele group met the predefined exposure-matching criterion relative to 50 mg in the 1-or-2-active-allele group, whereas 20 mg did not.The PBPK model quantified OCT1-related variability in sumatriptan disposition and supported 25 mg as a clinically feasible exploratory candidate for prospective evaluation in the 0-active-allele group.