Kate Gill (1), Helen Musther (1), Manoranjenni Chetty (1), Masoud Jamei (1), Malcolm Rowland (2) and Amin Rostami-Hodjegan (1, 2)
(1) Simcyp Limited, Blades Enterprise Centre, Sheffield, UK, (2) The University of Manchester, Manchester, UK
Objectives: PBPK models often report over-predicted maximum concentration (Cmax) for intravenous (IV) administration compared to observed in vivo sampled data. It is suggested that this discrepancy may be due to PBPK models reporting the concentration in the central venous compartment, rather than the concentration at the sampling site. The objective of this project was to develop a corrective model describing a “peripheral site” concentration-time profile.
Methods: A peripheral site model was developed assuming that the surrounding tissues around the sampling site contribute, to different degrees, to its concentration. The model utilised the tissue-specific concentration-time profiles output by the full-PBPK model in the Simcyp population-based simulator (V13), and tissue “flow” fractions as defined by Levitt (2004) [1]. Tissues used in defining the peripheral site were Skin, Adipose, Muscle and a “Shunt” to describe arterio-venous anastomoses, and the flow fractions were varied based on assumptions made about the arterial contribution to the “Shunt”. The model was applied to 7 different compounds where a Simcyp compound file and in vivo literature data following IV dosing were available. Predicted Cmax concentrations using the peripheral site model were compared to the observed Cmax at the same time point, and the difference in prediction accuracy compared to that of the central venous compartment concentration (“venous sampling”) was assessed.
Results: Application of the peripheral model improved predictions of the observed Cmax value compared to the “venous sampling” in Simcyp, in particular for early time points following IV dosing. All studies investigated showed a Cmax prediction within 2-fold of the observed value when using the peripheral site model. Changing the fractional contribution of the tissues resulted in an improvement for some compounds bringing them within a 0.8-1.25-fold range, while some compounds moved outside the 2-fold range, suggesting that the original fraction was preferable in the model selected.
Conclusions: The developed peripheral site model significantly improved predictions of Cmax after IV dosing for the compounds tested. The results suggest this model should be used when comparing the predicted and observed Cmax values from PBPK models.
References:
[1] Levitt DG. Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference. BMC Clin Pharmacol (2004) 4: 2.
Reference: PAGE 23 () Abstr 3209 [www.page-meeting.org/?abstract=3209]
Poster: Drug/Disease modeling - Absorption & PBPK