title: Application of a Physiologically Based Pharmacokinetic Model to Study Theophylline Metabolism and Its Interactions With Ciprofloxacin and Caffeine.
abstract: Theophylline is a commonly used bronchodilator. However, due to its narrow therapeutic range, moderate elevation of serum concentration can result in adverse drug reactions (ADRs). ADRs occur because of interhuman pharmacokinetic variability and interactions with coprescribed medicines. We developed a physiologically based pharmacokinetic (PBPK) model of theophylline, caffeine, and ciprofloxacin metabolisms to: examine theophylline pharmacokinetic variability, and predict population-level outcomes of drug-drug interactions (DDIs). A simulation-based equation for personalized dosing of theophylline was derived. Simulations of DDI show that calculated personalized doses are safe even after cotreatment with large doses of strong inhibitors. Simulations of adult populations indicate that the elderly are most susceptible to ADRs stemming from theophylline-ciprofloxacin and theophylline-caffeine interactions. Females, especially Asians, due to their smaller average size, are more susceptible to DDI-induced ADRs following typical dosing practices. Our simulations also show that the higher adipose and lower muscle fractions in females significantly alter the pharmacokinetics of theophylline or ciprofloxacin.
authors.affiliation: Biosciences & Biotechnology Division, Physics & Life Sciences Directorate, Lawrence Livermore National Laboratory Livermore California USA.
authors.forename: A
authors.initials: A
authors.lastname: Navid
authors.affiliation: Biosciences & Biotechnology Division, Physics & Life Sciences Directorate, Lawrence Livermore National Laboratory Livermore California USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ng
authors.affiliation: Biosciences & Biotechnology Division, Physics & Life Sciences Directorate, Lawrence Livermore National Laboratory Livermore California USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Wong
authors.affiliation: Biosciences & Biotechnology Division, Physics & Life Sciences Directorate, Lawrence Livermore National Laboratory Livermore California USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Lightstone
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001993:Bronchodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D057285:Precision Medicine; D012737:Sex Factors; D013806:Theophylline / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D002110:Caffeine; D002939:Ciprofloxacin; D013806:Theophylline