Drug-drug interaction between vonoprazan and imatinib: in vivo pharmacokinetics and in vitro metabolic inhibition characterization.

Abstract

1. Vonoprazan and imatinib may be co-prescribed in patients with acid-related disorders, but the pharmacokinetic consequences of this combination remain unclear.2. We evaluated the effects of vonoprazan on imatinib pharmacokinetics in rats and compared metabolic inhibition in human and rat liver microsomes.3. Rats (n = 6/group) received vehicle or vonoprazan (5.0 or 20.0 mg/kg) orally for 7 days, followed by imatinib (30.0 mg/kg). Imatinib and N-desmethyl imatinib were quantified by UPLC-MS/MS. Inhibition kinetics were examined in human (HLM) and rat liver microsomes (RLM).4. Imatinib AUC(0-t) increased by 37.2% and 63.7% at 5.0 and 20.0 mg/kg vonoprazan, respectively; the increase was significant at 20.0 mg/kg (p < 0.05). N-desmethyl imatinib AUC(0-t) decreased by 37.4% and 69.4% (both p < 0.05). IC50 values were 17.52 μM in HLM and 9.35 μM in RLM. Inhibition patterns were consistent with competitive inhibition in HLM and mixed-type inhibition in RLM, with apparent Ki values of 38.97 and 37.17 μM, respectively.5. Vonoprazan increased imatinib exposure in rats and inhibited microsomal metabolism. Species differences and uncertainty in the kinetic estimates limit quantitative extrapolation; clinical interaction studies are needed.