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Population pharmacokinetics of rifampin in the treatment of M ycobacterium tuberculosis in A sian elephants
Author(s) -
Egelund E. F.,
Isaza R.,
Brock A. P.,
Alsultan A.,
An G.,
Peloquin C. A.
Publication year - 2015
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12156
Subject(s) - pharmacokinetics , dosing , population , population pharmacokinetics , volume of distribution , pharmacology , covariate , minimum inhibitory concentration , medicine , nonmem , lag time , antibiotics , zoology , biology , statistics , microbiology and biotechnology , mathematics , environmental health , biological system
The objective of this study was to develop a population pharmacokinetic model for rifampin in elephants. Rifampin concentration data from three sources were pooled to provide a total of 233 oral concentrations from 37 A sian elephants. The population pharmacokinetic models were created using M onolix (version 4.2). Simulations were conducted using M odel R isk. We examined the influence of age, food, sex, and weight as model covariates. We further optimized the dosing of rifampin based upon simulations using the population pharmacokinetic model. Rifampin pharmacokinetics were best described by a one‐compartment open model including first‐order absorption with a lag time and first‐order elimination. Body weight was a significant covariate for volume of distribution, and food intake was a significant covariate for lag time. The median C max of 6.07 μg/mL was below the target range of 8–24 μg/mL. M onte C arlo simulations predicted the highest treatable MIC of 0.25 μg/mL with the current initial dosing recommendation of 10 mg/kg, based upon a previously published target AUC 0–24 / MIC > 271 (f AUC > 41). Simulations from the population model indicate that the current dose of 10 mg/kg may be adequate for MICs up to 0.25 μg/mL. While the targeted AUC/MIC may be adequate for most MIC s, the median C max for all elephants is below the human and elephant targeted ranges.