Purpose: The aim of this project was to better understand the predictive performance of the SimCYP PBPK model for both lymph and serum etanercept pharmacokinetics in the monkey.
Methods: Etanercept , a 150KDa fusion protein, was dosed to male cynomolgus monkeys. These animals underwent surgery to allow for lymphatic cannula placement in the thoracic duct. This enabled chronic sampling of lymphatic fluid for up to seven days post-dose Serum samples were also obtained at similar timepoints as lymph collection. Both lymph and serum samples were analyzed for etanercept concentration using an ELISA based assay.
Results: Lymph and serum pharmacokinetic data obtained in this model were compared to simulations of lymph and serum concentrations generated by SimCYP to evaluate the accuracy of the predictions. Simulation of etanercept serum concentrations were generally comparable to those observed. However, the variability in the observed concentrations of etanercept in lymphatic fluid made comparisons more challenging.
Conclusion: Examples using SimCYP PBPK models for large therapeutic molecules are scarce. This work compared SimCYP simulations to observed pharmacokinetic data in the monkey for etanercept. Successful prediction of large molecule pharmacokinetics in the monkey may ultimately provide insights to aid in the translation of pharmacokinetics from monkey to human.
Jon Ehrmann– Operations/Technical Manager II, Bristol-Myers Squibb Company, Lawrenceville, New Jersey
Anne Rose– Senior Research Scientist, Bristol-Myers Squibb Company, Princeton, New Jersey
Wendy Johnson– VETERINARY SCIENTIST II, Bristol-Myers Squibb Company, Pennington, New Jersey
Sophie Beyer– VETERINARY SCIENTIST II, Bristol Myers Squibb Comapny, Lawrenceville, New Jersey
Danielle Malone– Associate Veterinary Scientist I, Bristol-Myers Squibb Company, Lawrenceville, New Hampshire
Alexander Kozhich– Senior Principal Scientist, Bristol-Myers Squibb Company, Lawrenceville, New Jersey
Gerard Dalsglish– Associate Research Scientist II, Bristol-Myers Squibb Company, Lawrenceville, New Jersey
Aaron Yamniuk– Principal Scientist, Bristol-Myers Squibb Company, Lawrenceville, New Jersey
Kimberley Lentz– Director, Bristol-Myers Squibb Company, Lawrenceville, New Jersey