Posaconazole Tablet Pharmacokinetics: Lack of Effect of Concomitant Medications Altering Gastric pH and Gastric Motility in Healthy Subjects

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 7; pp. 4020 - 4025
• Main Authors: Kraft, Walter K., Chang, Peter S., van Iersel, Marlou L. P. S., Waskin, Hetty, Krishna, Gopal, Kersemaekers, Wendy M.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.07.2014
• Subjects: Adult; Antacids - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Clinical Therapeutics; Drug Interactions; Female; Gastric Acid; Gastric Acid - physiology; Gastrointestinal Motility; Gastrointestinal Motility - physiology; Healthy Volunteers; Histamine H1 Antagonists - pharmacology; Humans; Hydrogen-Ion Concentration; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Proton Pump Inhibitors - pharmacology; Tablets; Triazoles; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics; Young Adult; Human; Drug; Stomach; Motility; Healthy subject; Digestive system; Azole derivatives; Antifungal agent; Triazole derivatives; Dosage form; pH; Tablet; Pharmacokinetics; Posaconazole
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.02448-13

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 ( T max ), and apparent terminal half-life ( t 1/2 ) 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 (AUC 0–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 ( C max ) 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.