title: A physiologically based pharmacokinetic model for capreomycin.
abstract: The emergence of multidrug-resistant tuberculosis (MDR-TB) has led to a renewed interest in the use of second-line antibiotic agents. Unfortunately, there are currently dearths of information, data, and computational models that can be used to help design rational regimens for administration of these drugs. To help fill this knowledge gap, an exploratory physiologically based pharmacokinetic (PBPK) model, supported by targeted experimental data, was developed to predict the absorption, distribution, metabolism, and excretion (ADME) of the second-line agent capreomycin, a cyclic peptide antibiotic often grouped with the aminoglycoside antibiotics. To account for interindividual variability, Bayesian inference and Monte Carlo methods were used for model calibration, validation, and testing. Along with the predictive PBPK model, the first for an antituberculosis agent, this study provides estimates of various key pharmacokinetic parameter distributions and supports a hypothesized mechanism for capreomycin transport into the kidney.
authors.affiliation: Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, USA. brad.reisfeld@colostate.edu
authors.forename: B
authors.initials: B
authors.lastname: Reisfeld
authors.forename: C P
authors.initials: CP
authors.lastname: Metzler
authors.forename: M A
authors.initials: MA
authors.lastname: Lyons
authors.forename: A N
authors.initials: AN
authors.lastname: Mayeno
authors.forename: E J
authors.initials: EJ
authors.lastname: Brooks
authors.forename: M A
authors.initials: MA
authors.lastname: Degroote
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D001692:Biological Transport; D002207:Capreomycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009010:Monte Carlo Method; D014018:Tissue Distribution
chemical_list: D000995:Antitubercular Agents; D002207:Capreomycin