title: Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation.
abstract: The objective of these analyses was to assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF). The analyses included data from subjects without infection (phase 1) and patients with intra-abdominal infections (phase 2/3). Steady-state serum samples were collected from all subjects/patients (n = 577), while colon wall specimens (n = 23) and ELF specimens (n = 30) were obtained from subjects without infection. Tissue and serum data were simultaneously comodeled by using the BigNPAG program, and a four-compartment, open model with zero-order intravenous input and first-order elimination was employed. To examine the full range of tissue penetration and the associated probabilities of occurrence, a 9,999-subject Monte Carlo simulation was performed with two outputs, one for ELF penetration and one for colon wall tissue penetration. Data were well fit using models described above, with all r(2) values above 0.95. For subjects without infection, the median (5th and 95th percentiles) colon wall and ELF penetration ratios were 1.73 (0.160 and 199) and 1.15 (0.561 and 5.23), respectively. Simulation results predict that tissue penetration varies considerably and likely explain unexpected clinical outcomes for those patients infected with strains at margins of the MIC distribution.
authors.affiliation: Institute for Clinical Pharmacodynamics, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
authors.forename: John
authors.initials: J
authors.lastname: Speth
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ellis-Grosse
authors.forename: Keith R
authors.initials: KR
authors.lastname: Rodvold
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D003198:Computer Simulation; D004311:Double-Blind Method; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008954:Models, Biological; D009010:Monte Carlo Method; D000078304:Tigecycline; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline