A PBPK model for midazolam in four avian species

Abstract

A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.

Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modelling

“…A PBPK model is an excellent tool for the prediction of veterinary drug residues because it can be used to simulate continuous tissue residue time-concentration profiles and allows extrapolation across exposure routes, doses, and species. Several PBPK models have been developed to predict veterinary drug residues in food animals (Craigmill, 2003;Buur et al, 2006Buur et al, , 2008Cortright et al, 2009; A c c e p t e d M a n u s c r i p t al., 2011; 2014). All of these models successfully simulated the depletion of parent drug, with only two recent models describing the kinetics of their metabolites (Yang et al, 2013;Yang et al, 2015).…”

A physiologically based pharmacokinetic model for chickens exposed to feed supplemented with monensin during their lifetime

“…In the present model, leg muscles represented 14% (Fig. ) of the body weight on the 30th day, but other authors (Cortright et al ., ; Yang et al ., 2014b, ) attributed 40% of the body weight to muscles. If breast muscles and other muscles were added to this 14%, it is likely total muscle reached 40%.…”

“…The difference for fat can be attributed to the difficulty in measuring total fat and because fat is produced late in the growth cycle in farmed chickens. Furthermore, the fraction of fat described in the literature (Cortright et al ., ) represents a measure on the whole carcass, whereas in our study, it includes only abdominal fat. In the present model, leg muscles represented 14% (Fig.…”

“…Likewise, the cardiac output was scaled according to body weight (BW) but also the haematocrit ( H ) to turn the cardiac output Q CAR in terms of blood into the cardiac output Q TOT in terms of plasma: where cardiac output, Q CAR (Wideman, ), is expressed in L/h/kg BW and Q TOT is expressed in L/h. Fractions of the cardiac output reaching the organs (FracQc X ) were taken from the literature (Cortright et al ., ). From the difference between the cardiac output and the sum of blood flows to the liver, the fat and the leg muscle, a residual blood flow was calculated.…”

Use of a Monte Carlo analysis within a physiologically based pharmacokinetic model to predict doxycycline residue withdrawal time in edible tissues in swine

“…In veterinary medicine, the PBPK model has been used to study pharmacokinetics (Gustafson and Thamm 2010) and tissue distribution (Brocklebank et al 1997;Craigmill 2003;Cortright et al 2009). Other reports have used the PBPK model to predict residue withdrawal time (Buur et al 2006(Buur et al , 2008Yuan et al 2011).…”