The effects of a short course of antibiotics on alvimopan and metabolite pharmacokinetics.
Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C(max) by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.
Clinical Pharmacology/Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. ginny.d.schmith@gsk.com
Virginia D
VD
Schmith
Brendan M
BM
Johnson
Lakshmi S
LS
Vasist
Dennis L
DL
Kelleher
Deborah A
DA
Hewens
Malcolm A
MA
Young
Vanessa
V
Ameen
George E
GE
Dukes
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D055815:Young Adult
D000900:Anti-Bacterial Agents; D005765:Gastrointestinal Agents; D010880:Piperidines; D017450:Receptors, Opioid, mu; D002939:Ciprofloxacin; C419502:alvimopan