title: Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats.
abstract: The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.|Pharmacy Department, University Clinical Hospital of Valencia, Valencia, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Pérez-Pitarch
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Guglieri-López
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Nacher
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Merino
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Merino-Sanjuan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D064704:Levofloxacin / Q000494:pharmacology*; D008297:Male; D044342:Malnutrition / Q000378:metabolism*; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D012709:Serum Albumin / Q000032:analysis
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012709:Serum Albumin; D064704:Levofloxacin; D000069347:Erlotinib Hydrochloride
keywords: absorption; drug interaction; erlotinib; levofloxacin; undernutrition