s-1743 and cycloguanil

CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates. This study aimed to evaluate the effect of tegoprazan on the pharmacokinetics (PK) of a CYP2C19 substrate, proguanil, compared with vonoprazan or esomeprazole.. A two-part, randomized, open-label, two-sequence, three-period crossover study was conducted in 16 healthy CYP2C19 extensive metabolizers (eight subjects per part). In each period, a single oral dose of atovaquone/proguanil 250/100 mg was administered alone or co-administered with tegoprazan 50 mg, esomeprazole 40 mg (Part 1 only) or vonoprazan 20 mg (Part 2 only). The plasma and urine concentrations of proguanil and its metabolite, cycloguanil, were measured up to 48 h post-dose. PK parameters were calculated using a non-compartmental method and compared between administered alone and co-administered with tegoprazan, vonoprazan or esomeprazole.. Co-administration of tegoprazan did not significantly affect the systemic exposure of proguanil and cycloguanil. In contrast, co-administration of vonoprazan or esomeprazole increased proguanil systemic exposure and decreased cycloguanil systemic exposure, and the magnitude of the corresponding change was greater with esomeprazole co-administration than vonoprazan co-administration.. Tegoprazan, unlike vonoprazan and esomeprazole, exhibited negligible CYP2C19-mediated PK interaction. It suggests that as an alternative to other acid-reducing agents, tegoprazan can be used concomitantly with CYP2C19 substrates in clinical settings.. Clinicaltrials.gov identifier: NCT04568772 (Registered on September 29, 2020).

Topics: Atovaquone; Cross-Over Studies; Cytochrome P-450 CYP2C19; Drug Interactions; Esomeprazole; Humans; Proguanil; Reducing Agents

Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate.. Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry.. Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil.. Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates.

Topics: Adult; Area Under Curve; Atovaquone; Chromatography, Liquid; Cytochrome P-450 CYP2C19; Drug Combinations; Esomeprazole; Humans; Male; Proguanil; Proton Pump Inhibitors; Pyrroles; Sulfonamides; Tandem Mass Spectrometry; Triazines; Young Adult