Manuel Prado – Velasco
Empresarios Agrupados Internacional
Introduction and objectives: According EMEA bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form, and becomes available at the site of action [1]. Due to the difficulty to perform that measurement, the rate and amount of the active substance delivered to the systemic circulation are accepted as surrogate indices.
The amount related bioavailability, F, is defined as the proportion of a drug which is absorbed and available to produce systemic effects. Although F could vary with time, standard mathematical equations neglect time dependency of F, and use an asymptotic or steady-state values for unique and multiple drug dose, respectively. Additional equations are needed in the case of non-linear clearance, both for single and multiple doses [2]. More complications emerge in the case of extensive first-pass effect in lungs [1].
The key point is that despite the importance of bioavailability in bioequivalence studies, current procedures are limited to stationary values and systemic circulation. This study presents a novel approach to calculate F(t) in the site of action by means of PBPK models.
Methods: The following stages define the procedure used to develop the approach
- Current mathematical equations to calculate F, with emphasis in their assumptions, are firstly reviewed.
- New mathematical formulations for F(t) are comprehensively presented. These equations have been implemented into signal computing elements of the PhysPK© biosimulation system’s Widgets library.
Several scenarios were defined to compare the new equations against standard ones using a Tacrolimus PBPK model based on a previous published one [3]. The Tacrolimus model was validated against the data set of a pediatric clinical study carried out with 20 patients. A non-Compartmental Analysis (NCA) was finally executed to calculate standard F values, which were compared to the F values provided by the PBPK model
Results: The novel equations for F gave steady-state and asymptotic values equal to those ones of standard equations in systemic circulation, both for single and multiple dose scenarios, and for linear and non-linear clearance, through PBPK model simulations.
The F values obtained in the NCA with the data set values of the clinical study were in agreement with the simulation values of the adjusted Tacrolimus PBPK model, both for standard and new equations.
In addition, the simulation results of the adjusted Tacrolimus PBPK model included temporal values of F(t) in target anatomical regions, kidneys and liver.
Conclusions: It has been defined a new approach to measure the dynamic value of bioavailability, F(t), based on population fitted PBPK models and new mathematical formulations of F(t). The procedure was implemented in the PhysPK© biosimulation software, which makes easy the addition of new computational metrics by means of an object-oriented, multilevel modelling, and graphic user interface system.
Data of Tacrolimus plasmatic concentrations from a 20 patient’s clinical study were used to validate a Tacrolimus PBPK model successfully. This model, implemented in PhysPK, was the basis for the execution of a computational experiment that run simultaneously non-compartment calculations (NCA) and compartmental simulations, giving standard and novel bioavailability F(t) values, besides other standard plasmatic metrics (Cmax, AUC-12h, etc.).
Results shown that standard equations of F for steady – state and asymptotic plasmatic values computed from compartmental simulations accurately match to NCA values. The new equations for F(t) delivered the same accurate values of steady – state and asymptotic values, but they added their temporal evolution and the availability to measure it other anatomic regions like kidneys and liver.
Despite temporal values of F were not contrasted against experimental temporal values different of asymptotic and steady – state scenarios, the good agreement to the standard NCA values, together with the accurate predictions of a well-defined and validated PBPK model, suggest that this physiology based model approach to calculate the bioavailability could be considered an alternative technique to current standards in those cases where the dynamics of F could have a significant influence in therapeutic response.
References:
[1]. Toutain, P.L. and a. Bousquet-Mélou, Bioavailability and its assessment. Journal of veterinary pharmacology and therapeutics, 2004. 27: p. 455-66.
[2]. Berrozpe, J.D., J.M. Lanao, and C.P. Guitart, eds. Tratado general de Biofarmacia y Farmacocinética. Volumen I. 2013, Editorial Síntesis. 700 p.
[3]. Gérard, C., et al., Determination of the most influential sources of variability in tacrolimus trough blood concentrations in adult liver transplant recipients: a bottom-up approach. The AAPS journal, 2014. 16: p. 379-91.
Reference: PAGE 27 (2018) Abstr 8556 [www.page-meeting.org/?abstract=8556]
Poster: Methodology - New Modelling Approaches