(T1130-11-64) Physiologically Based Pharmacokinetic Modelling to Predict the Pharmacokinetics of Aspirin and Its Metabolite Salicylic Acid after Intravenous, Oral, and Rectal Administration

Purpose: Aspirin (ASP) is a small molecule anti-inflammatory drug used to treat inflammation, pain, fever, and for the prevention of cardiovascular events. It is rapidly converted to salicylic acid (SA) in the liver, intestine, kidney, etc., by carboxylesterases. In the United States and worldwide different formulations of ASP are available in the market such as immediate-release tablets, enteric-coated tablets, and suppositories. The modelling and simulation of the pharmacokinetics of drug molecules are of great interest to the pharmaceutical industry, academia, and regulatory agencies. Physiologically based pharmacokinetic models encompass drug-specific information, formulation characteristics and system (physiology) information which can be used as a tool to justify formulation decisions. Thus, in this research, we developed a PBPK model to predict the pharmacokinetics of ASP and its metabolite (SA after intravenous (IV), oral (PO) and rectal administration.

Methods: The drug pharmacokinetic information was collected from published literature reports of intravenous, oral and rectal administration studies and digitalized using GetData Graph Digitalizer version 2.26.0.20. The modelling and simulations were carried out using the Simcyp Simulator V21. The models are parameterized to include drug-specific parameters related to physicochemical properties, binding, distribution, and elimination specific to ASP and SA (either predicted or taken from the literature). A full PBPK distribution model was employed to run the simulations in the Healthy Volunteers (HV) population for both ASP and SA. To describe the oral pharmacokinetics, the ADAM model was parameterized and further utilized to run the simulations for oral solutions, the immediate-release (IR) and enteric-coated (ER) tablet formulations. After successful verification of the PBPK model for IV and PO administration, it was connected to Simcyp’s mechanistic rectal absorption model (MechRAM) to carry out the simulations. The MechRAM has recently been implemented in the Simcyp simulator. It considers the human lower rectum physiology description. Various processes including drug ionization, permeability and partitioning in the mucus layer and rectal epithelium are considered (Yuri Dancik, 2021). The disposition of intravenous (IV) pharmacokinetics of ASP at a dose of 650 mg was reported by Rowland et al (Rowland & Riegelman, 1968) whereas the oral pharmacokinetics studies reported by Dei Cas et al were used to perform the modelling and verification of ADAM model (Dei Cas et al., 2021; Rowland & Riegelman, 1968). Further, the in vitro data reported by Katona et al. was used to predict the pharmacokinetics of Aspirin Protect 100 mg ER tablet after oral administration(Katona et al., 2022). Furthermore, the in vitro release data reported for two different ASP formulations and in vivo cumulative urine amounts of SA after rectal administration in humans (Parrott, 1975) were utilized to parameterize/verify the MechRAM model.

Results: Figure 1 compares the simulated and observed profiles from Rowland et al. (Rowland & Riegelman, 1968). The observed data is within the 5^th-95^th percentile of predicted plasma concentrations time profiles for both IV and oral administration of 650 mg solution formulations. In Figure 2 the simulated time vs. plasma concertation profiles and observed data for the reported study by Dei Cas et al. for 100 mg immediate-release (IR) and 100 mg enteric-coated (EC) ASP formulations are shown. It is evident from these simulation results that the observed data were satisfactorily captured by the PBPK model. The Parrot study compares the effect of particle size on the absorption of ASP from two different formulations of a theobroma oil base (Parrott, 1975). The study reports the cumulative total salicylates in urine after hydrolysis of samples. To predict the observed cumulative urine amounts the MechRAM model is parameterized with permeabilities, partition coefficients and reported in vitro release data. In Figure 3 the cumulative total salicylate excreted predicted profiles and observed data for two different formulations administered rectally in human subjects and the observed in vivo absorption rate of the powder formulation is faster than the disk formulation (low surface area) which was picked up well by the MechRAM model and agrees with the in vitro release behaviour.

Conclusion: The PBPK model predictions are in good agreement with reported clinical trials pharmacokinetics data in the adult populations after dose administration via the intravenous, oral, and rectal routes. The developed models can be further utilized to evaluate and optimize the performance of new dosage forms, also it can be extended to special populations such as paediatrics and pregnant women.

References: Dei Cas, M., Rizzo, J., Scavone, M., Femia, E., Podda, G. M., Bossi, E., Bignotto, M., Caberlon, S., Cattaneo, M., & Paroni, R. (2021). In-vitro and in-vivo metabolism of different aspirin formulations studied by a validated liquid chromatography tandem mass spectrometry method. Scientific Reports, 11(1), 10370. https://doi.org/10.1038/s41598-021-89671-w
Katona, M. T., Kakuk, M., Szabó, R., Tonka-Nagy, P., Takács-Novák, K., & Borbás, E. (2022). Towards a Better Understanding of the Post-Gastric Behavior of Enteric-Coated Formulations. Pharm Res, 39(1), 201-211. https://doi.org/10.1007/s11095-021-03163-0
Parrott, E. L. (1975). Influence of particle size on rectal absorption of aspirin. J Pharm Sci, 64(5), 875-880.
Rowland, M., & Riegelman, S. (1968). Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. Journal of Pharmaceutical Sciences, 57(8), 1313-1319. https://doi.org/https://doi.org/10.1002/jps.2600570807
Yuri Dancik, N. M., Arran Hodgkinson,Santosh Puttrevu,Sebastian Polak. (2021). Development and Verification of a Novel PBPK Model of Rectal Drug Absorption. AAPS Pharm Sci 360 Annual Meeting

Disclaimer: Aspirin is a registered trademark of Bayer.
Funding statement: The work did not receive any external funding.
Conflict of interest: All authors are employees of Certara UK Ltd.


Figure 1.The pharmacokinetics of ASP and SA (simulated vs observed): intravenous administration of 650 mg ASP solution (A) and resultant SA levels (B), oral administration of 650 mg ASP solution(C) and resultant SA systemic levels


Figure 2. ASP and SA model predictions for oral administration of 100 mg IR (A&B) and EC (C&D) tablets (Dei Cas et al )


Figure 3. Parrot study total cumulative Salicylate excreted vs time profiles for (A) Powder formulation (B) Disk formulation (verification)