title: Effect of Multiple Oral Doses of the Potent CYP3A4 Inhibitor Clarithromycin on the Pharmacokinetics of a Single Oral Dose of Vonoprazan: A Phase I, Open-Label, Sequential Design Study.
abstract: OBJECTIVE
  This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan.
  
  
  METHODS
  During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3-9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul). Safety was also assessed.
  
  
  RESULTS
  Following administration, vonoprazan was rapidly absorbed (time to reach Cmax, 2 h), consistent with its known pharmacokinetic profile. This was unchanged in the presence of clarithromycin. Plasma concentrations declined thereafter, with a mean apparent terminal elimination half-life of 7.2 h on day 1 and 9.4 h on day 8. Small-to-moderate increases (1.6- and 1.4-fold) in mean AUC and Cmaxof vonoprazan, respectively, were observed following clarithromycin. In contrast, AUC and Cmaxfor vonoprazan metabolites decreased, except for M-IV-Sul, which increased approximately 2.1- and 1.5-fold, respectively. Overall, vonoprazan was well tolerated, with mild or moderate treatment-emergent adverse events occurring in six (37.5%) subjects receiving either vonoprazan and/or clarithromycin.
  
  
  CONCLUSIONS
  Modest increases in plasma concentrations of the potent CYP3A4 inhibitor clarithromycin and vonoprazan were observed during coadministration, however these differences were not considered clinically significant. Vonoprazan had a favorable safety and tolerability profile, and no serious adverse events were reported. CLINICALTRIALS.GOV: NCT02774902.
authors.affiliation: Takeda Development Centre Europe Ltd, 61 Aldwych, London, WC2B 4AE, UK. helen.jenkins@takeda.com.
authors.forename: Helen
authors.initials: H
authors.lastname: Jenkins
authors.affiliation: Takeda Development Centre Europe Ltd, 61 Aldwych, London, WC2B 4AE, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Jenkins
authors.affiliation: Biotrial S.A., Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Patat
mesh_terms: D000328:Adult; D019540:Area Under Curve; D017291:Clarithromycin / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D011758:Pyrroles / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D065692:Cytochrome P-450 CYP3A Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; D017291:Clarithromycin