title: Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects.
abstract: Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥ 10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA walter.kraft@jefferson.edu.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chang
authors.affiliation: MSD, Oss, Netherlands.
authors.forename: Marlou L P S
authors.initials: ML
authors.lastname: van Iersel
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey, USA.
authors.forename: Hetty
authors.initials: H
authors.lastname: Waskin
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey, USA.
authors.forename: Gopal
authors.initials: G
authors.lastname: Krishna
authors.affiliation: MSD, Oss, Netherlands.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Kersemaekers
mesh_terms: D000328:Adult; D000863:Antacids / Q000494:pharmacology; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004347:Drug Interactions; D005260:Female; D005744:Gastric Acid / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000502:physiology*; D064368:Healthy Volunteers; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D013607:Tablets; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000863:Antacids; D000935:Antifungal Agents; D006634:Histamine H1 Antagonists; D054328:Proton Pump Inhibitors; D013607:Tablets; D014230:Triazoles; C101425:posaconazole