Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir
Karen‐Margrethe Pedersen, Anna Katrina Jógvansdóttir Gradel, Trine Pagh Ludvigsen, Berit Østergaard Christoffersen, Caroline Amalie Fuglsang-Damgaard, Kristian Moss Bendtsen, Suzi Høgh Madsen, Valentina Manfé, Hanne Hoffmann Frølund Refsgaard
Abstract
Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model. Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model. AT A Glance CommentaryPedersen K-M, et al.BackgroundPrediction of human pharmacokinetics is typically done by allometric scaling on data from several animal species. This study applied single-species allometric scaling on data from two pig breeds to assess the predictions for liraglutide, insulin aspart and insulin detemir.Translational SignificanceReliable predictions were achieved with single-species allometric scaling, suggesting that fewer species and animals can be used to assess the translatability of therapeutic proteins. Furthermore, depending on the desired pharmacokinetic properties of the compound, pig breed and injection region should be taken into consideration in pre-clinical studies since these factors affected the pharmacokinetics of the selected proteins. Pedersen K-M, et al. Prediction of human pharmacokinetics is typically done by allometric scaling on data from several animal species. This study applied single-species allometric scaling on data from two pig breeds to assess the predictions for liraglutide, insulin aspart and insulin detemir. Reliable predictions were achieved with single-species allometric scaling, suggesting that fewer species and animals can be used to assess the translatability of therapeutic proteins. Furthermore, depending on the desired pharmacokinetic properties of the compound, pig breed and injection region should be taken into consideration in pre-clinical studies since these factors affected the pharmacokinetics of the selected proteins.