Helen Musther (1), Kate Gill (1), Lu Gaohua (1), Shriram Pathak (1) & Masoud Jamei (1)
(1) Simcyp Limited, Blades Enterprise Centre, Sheffield, UK
Objectives: A corrective model to account for the observation that physiologically-based pharmacokinetic (PBPK) models often over-predict Cmax for intravenous (i.v.) administration compared to in vivo sampling data has previously been presented [1]. The initial validation was limited to only seven compounds. The objective of this study was to extend the validation to additional compounds with varying physiochemical properties.
Methods: A peripheral site model has been developed and implemented within the Simcyp Simulator based on anatomy and physiology governing the blood supply at the site of sampling [1]. Additional compound datasets were identified where data required for modelling a compound and clinical studies with i.v. dosing and early sampling time points were available. Comparisons were made between predicted and in vivo observed Cmax values for the central venous and peripheral site models.
Results: Physicochemical and in vitro metabolism data for six compounds (Clarithromycin, Dextromethorphan, Dextrorphan, Erythromycin, Lidocaine and Tramadol) with at least one relevant clinical i.v. study were collated for further performance verification. All studies investigated showed a Cmax prediction within 2-fold of the observed value when using the peripheral site concentration, with many showing a marked improvement compared to the central venous concentration. The impact of using the corrective model may depend on the compound properties and the length of the intravenous administration.
Conclusions: Additional successful validation was performed for a model that allows a more realistic comparison of the predicted concentrations at a peripheral sampling site to those taken in clinical trials, particularly at early sampling time points and for compounds known to distribute into tissues. These models can be built into PBPK platforms to improve Cmax predictions and potentially account for factors (such as effect of heat, variation in adipose and muscle content of the body) that may affect the initial mixing of the blood at the site of sampling and hence the simulated drug concentrations in blood or plasma at early time points.
References:
[1] Gill et al., 2014 PAGE meeting.
Reference: PAGE 24 (2015) Abstr 3473 [www.page-meeting.org/?abstract=3473]
Poster: Drug/Disease modeling - Absorption & PBPK