A physiologically based pharmacokinetic model for valnemulin in rats and extrapolation to pigs.
A flow-limited, physiologically based pharmacokinetic (PBPK) model for predicting the plasma and tissue concentrations of valnemulin after a single oral administration to rats was developed, and then the data were extrapolated to pigs so as to predict withdrawal interval in edible tissues. Blood/tissue pharmacokinetic data and blood/tissue partition coefficients for valnemulin in rats and pigs were collected experimentally. Absorption, distribution and elimination of the drug were characterized by a set of mass-balance equations. Model simulations were achieved using a commercially available software program. The rat PBPK model better predicted plasma and tissue concentrations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, lung and muscle were 0.96, 0.94, 0.96, 0.91 and 0.91, respectively. The rat model parameters were extrapolated to pigs to estimate valnemulin residue withdrawal interval in edible tissues. Correlation (R(2) ) between predicted and observed liver, kidney and muscle were 0.95, 0.97 and 0.99, respectively. Based on liver tissue residue profiles, the pig model estimated a withdrawal interval of 10 h under a multiple oral dosing schedule (5.0 mg/kg, twice daily for 7.5 days). PBPK models, such as this one, provide evidence of the usefulness in interspecies PK data extrapolation over a range of dosing scenarios and can be used to predict withdrawal interval in pigs.
Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
L G
LG
Yuan
X Y
XY
Luo
L X
LX
Zhu
R
R
Wang
Y H
YH
Liu
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D004224:Diterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule / Q000662:veterinary; D005260:Female; D008297:Male; D008954:Models, Biological; D051381:Rats / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013552:Swine / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000662:veterinary
D000900:Anti-Bacterial Agents; D004224:Diterpenes; C117845:valnemulin