Using physiologically based pharmacokinetic modelling to optimize repaglinide and irbesartan dosing in Chinese population with SLCO1B1 polymorphism.

The SLCO1B1 c.521T>C variant alters the hepatic uptake transporter OATP1B1; irbesartan, an inhibitor of this transporter, increases repaglinide exposure, with a modelled effect that differs according to genotype.

The authors built physiologically based pharmacokinetic (PBPK) models of repaglinide and irbesartan to describe their drug-drug interaction in a Chinese population carrying the SLCO1B1 c.521T>C polymorphism. The model, developed from literature and laboratory data then evaluated against published clinical studies, accurately reproduced plasma concentration-time profiles, AUC, Cmax and Tmax. Simulations predicted that co-medication with irbesartan significantly increased repaglinide exposure in c.521TT subjects compared with c.521TC subjects. With 300 mg irbesartan in c.521TT carriers, the model recommends either giving repaglinide 2 h earlier or 4 h later (AUC0-inf ratio 0.90-0.97), or reducing the dose to 60-70% of the initial dose (AUC0-inf ratio 0.99-1.10), depending on available dosage strengths.

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

The practical value is real: two simple operational options - shifting the dosing interval or reducing the dose - where most SLCO1B1 work stops at documenting increased exposure. The limitation is structural: this is an in silico prediction calibrated on published data, with no prospective cohort and no measured glycaemic or hypoglycaemic endpoint, so these AUC ratios cannot be translated into demonstrated clinical benefit. What I retain is the vigilance signal in hypertensive diabetic patients on this combination, bearing in mind that the direction of the genotype effect reported here deserves experimental confirmation before any prescribing use.

Analysis by Dr Thibaut Benquey