Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models From acslX to Berkeley Madonna, MATLAB, and R Language: Oxytetracycline and Gold Nanoparticles As Case Examples

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (P s) for noneliminating tissues were calculated according to the area method, while the P s for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra-label manner using the PBPK modeling.

MAPE false(% false) = \frac{1}{N} \sum_{i = 1}^{N} \frac{| C_{oi} - C_{pi} |}{C_{normaloi}} \times 100 %,

Section: Methodsmentioning

confidence: 99%

Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

Yang

Shi

et al. 2018

“…According to World Health Organization guidelines (WHO, ), if the simulations matched the measured kinetic profiles well and were generally within a twofold range of the measured values, the model was considered reasonable and validated. The sensitivity and linear regression analyses were carried out using the method reported previously (Cheng, Riviere, Monteiro‐Riviere, & Lin, ; Elwell‐Cuddy, Li, KuKanich, & Lin, ; Lin et al, ; Zeng et al, ). The linear regression analysis was based on the mean value at each time point.…”

Section: Methodsmentioning

confidence: 99%

“…validated. The sensitivity and linear regression analyses were carried out using the method reported previously (Cheng, Riviere, Monteiro-Riviere, & Lin, 2018;Elwell-Cuddy, Li, KuKanich, & Lin, 2018;Lin et al, 2017;Zeng et al, 2017). The linear regression analysis was based on the mean value at each time point.…”

Section: Model Fittedmentioning

confidence: 99%

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

Mainquist-Whigham

Karriker

et al. 2019

Self Cite

Penicillin G is widely used in food‐producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal‐derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow‐derived meat products.

“…Mass balanced differential equations were used to illustrate the rate of change in each of the designed tissue compartments, and only methadone not bound to plasma proteins was considered to be available for use by the body. Berkeley Madonna™ (Version 8.3.23.0; University of California, Berkeley, CA, USA) was utilized to construct the model and conduct simulations, a software that has been used successfully in other PBPK models (Lin et al., ). The model code is contained within the Appendix and is also available on our center's website (http://iccm.k-state.edu/).…”

Section: Methodsmentioning

confidence: 99%

The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds

Elwell-Cuddy

KuKanich

Lin

2018

Self Cite

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna™ was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R > 0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24-hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed-specific parameters.