Model-informed dose optimization of etrasimod in ulcerative colitis across CYP2C9 genotypes and hepatic impairment.

Etrasimod is metabolized by cytochrome P450 2C9: a CYP2C9 poor metabolizer phenotype and hepatic impairment both reduce its clearance and raise systemic exposure, with the largest effect when the two are combined.

The authors built a physiologically based pharmacokinetic (PBPK) model of etrasimod, an oral sphingosine-1-phosphate receptor modulator approved for moderate-to-severe ulcerative colitis, and verified it against in vitro metabolism data and single-dose, multiple-dose and drug-drug interaction clinical pharmacokinetic data. The model was then extrapolated to Chinese populations stratified by CYP2C9 genotype and severity of hepatic impairment. At the approved 2 mg once-daily dose, predicted median steady-state AUC0-24 was 1976.95 ng·h/mL (95% prediction interval 975.78-4144.29) in Caucasian subjects and 1988.82 ng·h/mL (814.91-4244.10) in Chinese subjects, with most predicted parameters falling within a twofold error range. The largest exposure increase was seen in CYP2C9 poor metabolizers with Child-Pugh C hepatic impairment (67% higher steady-state AUC). Model-based exposure matching supported dose reduction to 1.5 mg once daily for most affected subgroups and to 1 mg once daily for that most-exposed subgroup.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The proposed regimens are entirely simulation-derived: no patient actually received the reduced dose, and a twofold prediction tolerance is wide when the adjustment under discussion spans 2 mg down to 1 mg. The study reports no star alleles and no allele frequencies, so it does not indicate how many patients would be affected in practice. Before genotyping CYP2C9 routinely ahead of etrasimod, measured exposures in genuinely treated poor metabolizers, and confirmation outside Chinese populations, would be needed.

Analysis by Dr Thibaut Benquey