Virtual Bioequivalence Assessment of Two Tramadol Formulations using the Advanced Dissolution Absorption and Metabolism (ADAM) model via Simcyp R Package
Janak Wedagedera, Theresa Cain, Shriram Pathak, Masoud Jamei
Simcyp (a Certara company)
Objectives: A qualified PBPK model of tramadol has previously been used to simulate virtual bioequivalence (BE) trials using a random error approach [1]. We aim to expand this approach using the Simcyp16 R package to assess the impact of inter-occasion variability on the bioequivalence (BE) of two tramadol formulations.
Methods: Mechanistic absorption models such as the Advanced Dissolution Absorption and Metabolism (ADAM) model implemented within population based Physiology-Based Pharmacokinetic (PBPK) models are useful tools in integrating various physiological parameters and formulation specifications affecting drug products. An important feature of PBPK modelling is accounting for within- and between- subject variability, when reference and test formulations are compared from a BE perspective.
Previously, PBPK models of tramadol for different formulations were developed and qualified. Then random residuals were added to their PK parameters to simulate virtual BE of the two formulations. In this work, the models are used to assess the formulations BE when inter-occasion variability are incorporated within parameters affecting the GI tract motility. In order to add inter-occasion variability the Simcyp Simulator parameters were modified using the Simcyp16 R package where variability is added to each individual gastric emptying time, small intestine transit time, and colon transit time. This process is repeated for each formulation for a specified number of times. Then the Bioequivalence between the test and reference formulations was assessed using the AUC, Cmax and Tmax values.
Results: Using the Simcyp16 R package the previously qualified PBPK model of tramadol was used for various formulations for 16 virtual subjects using a healthy volunteer population. Each subject was simulated 10 times where their gastric emptying time, small intestine transit time, and colon transit time were changed using a normal distribution by the assigned mean and a 10% CV. Then to assess the BE of these formulations the PK parameters, namely AUC, Cmax and Tmax were compared and the acceptable ranges based on the upper and lower bound of dissolution profiles were determined.
Conclusions: Mechanistic absorption models incorporated within population-based PBPK model can be used to run virtual BE studies and evaluate reference and test formulations. Such approach allows incorporation of inter-occasion variability in parameters that affect the formulations performance. These simulations may inform the optimal design of BE studies.
References:
[1] Pathak et al., Establishment of Virtual Bioequivalence Using Population-Based PBPK Modelling: Application to the Setting of Dissolution Limits, CRS Annual Meeting 2016, Edinburgh, Scotland, UK.