Christiane Dings (1) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Objectives: Acetylsalicylic acid (ASA) is a well-known antipyretic drug and has been studied and used for its anti-thrombotic effect since the 1960s [1]. However, there is little knowledge about the pharmacokinetic/pharmacodynamic (PK/PD) relationship between ASA and platelet aggregation. Therefore, the aim of the work was to develop a PK/PD model of ASA and its major metabolite salicylic acid (SA) including thromboxane B2 (TxB2) as a biomarker for the antithrombotic effect of ASA.
Methods: PK and PD data was digitized from a study comparing PK and PD after doses of 5 to 80 mg ASA as instant release (IR) and 20 to 325 mg ASA as extended release (ER) formulations in 50 volunteers [2]. The data included 70 and 85 mean plasma concentrations of ASA and SA, respectively, and 77 mean measurements of TxB2 inhibition. The model was evaluated using digitized data from another PK/PD study of ASA [3]. Deterministic simulations were performed to investigate different treatment regimens ensuring sufficient inhibition of the platelet aggregation throughout the day (>95% TxB2 inhibition at steady-state) [3]. Modeling and simulation was performed using NONMEM (version 7.2.0) without interindividual variability, but considering residual variability.
Results: For ASA and SA a one- and two-compartment model, respectively, described the pharmacokinetics best. A compartment between the absorption compartment and the central compartments of ASA and SA was included to describe the presystemic metabolism and pharmacodynamic effect of ASA. All absorption, distribution and elimination processes of ASA and SA were described as first-order processes. TxB2 levels were described by a turnover model with zero-order input, first-order output. Under ASA treatment a second-order elimination depending on ASA and TxB2 levels was incorporated. The model successfully predicted the plasma TxB2 levels of the evaluation dataset. Simulations revealed that the administration of 97 mg (IR) twice daily and 169 mg (ER) once or 49 mg twice daily resulted in a sufficient platelet aggregation. Peak ASA plasma levels ensuring sufficient platelet inhibition were lower for the ER formulation.
Conclusion: A PK/PD model for ASA and its major metabolite SA was presented for the first time. The model demonstrated a good predictive performance. Deterministic simulations confirmed an advantage of the ER formulation over the IR formulation.
References:
[1] Weiss H J et al. The discovery of the antiplatelet effect of aspirin: a personal reminiscence. Journal of Thrombosis and Haemostasis (2003), 1(9): 1869-1875.
[2] Patrick J et al. A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation. Postgraduate Medicine (2015), 127(6):573-80.
[3] Nagelschmitz J et al. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers. Clinical Pharmacology: Advances and Applications (2014), 6: 51–59.
Reference: PAGE 25 (2016) Abstr 5762 [www.page-meeting.org/?abstract=5762]
Poster: Drug/Disease modeling - Other topics