Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid
Cuesta-Gragera A1, Navarro C1, González-Álvarez I2, García-Arieta, A3#, Iñaki F. Trocóniz IF4, Casabó VG1, Bermejo M2
1 Department of Pharmacy and Pharmaceutical Technology. University of Valencia. Av. Vicente Andrés Estellés s/n 46100 Burjassot, Valencia, Spain 2 Department of Engineering, Pharmacy Section, Miguel Hernandez University, Carretera Alicante Valencia km 87, 03550 San Juan de Alicante, Alicante, Spain 3 Pharmacokinetics Service. Division of Pharmacology and Clinical Evaluation. Human Use Medicines. Spanish Agency of Medicines and Medical Devices (AEMPS). Campezo 1. Madrid E-28022 Spain 4 Department of Pharmacy and Pharmaceutical Technology. School of Pharmacy . University of Navarra. Irunlarrea 1. Pamplona. Spain # This article reflects the author’s personal opinion and not necessarily the policy or recommendations of the AEMPS.
Due to the different criteria of the European and American Guidelines for bioequivalence, our investigation group had studied theoretical drugs with different kind of metabolism, to define the most sensitive analyte (parent compound or metabolites) for in vivo bioequivalence studies.
In this work we studied a drug with first-pass hepatic and intestinal metabolism and Michaelis-Menten kinetics that lead to the formation of two main metabolites in two generations (first and second generation metabolites).
Objectives:1) to present a semi-physiological model for acetylsalicylic acid (ASA), 2) to validate the model and 3) to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in the dissolution constant (KD) of the formulation.
Methods:A semi-physiological model was proposed to represent this pharmacokinetic behavior. The chosen compound was the acetylsalicylic acid (ASA). The semi-physiological model was developed in NONMEM VI using ASA parameters from bibliography. The first aim was to present a semi-physiological model for ASA, showing its sequential metabolism. The second aim was to validate this model to know if it represents the ASA behavior. The validation was made comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000mg) and at 6 decreasing in vivo dissolution rate constants of the test formulations (kD 8 to 0.25h-1) to achieve the third aim of the study: to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in the formulations performance.
Results:The validation results showed that the concentration-time curves obtained with the simulations fitted the published experimental data, so we consider that the model is validated. The bioequivalence results showed that the parent drug was the most sensitive analyte for bioequivalence trials. The parent drug (ASA) was the first analyte that showed a great decrease in Cmax ratio between test and reference formulation. In addition, in most scenarios the parent drug was the first analyte that showed a decrease in AUC ratio. The exception to this occurred at doses of 1000 and 3000mg when kD was 0.25h-1: in these two cases, the AUC ratio of the first metabolite (salicylic acid) was a little bit lower than the ratio of ASA.
Conclusions:1) The proposed model was considered validated. 2) The parent compound (ASA) was more sensitive than its main metabolites (SA and SU) to changes in the KD of formulations.
References:
[1] Bradley, S.E., Ingelfinger, F.J., Bradley, G.P., Curry, J.J., 1945. The estimation of hepatic blood flow in man. The Journal of Clinical Investigation 24, 890-897.
[2] Brantmark, B., Wahlin-Boll, E., Melander, A., 1982. Bioavailability of acetylsalicylic acid and salicylic acid from rapid-and slow-release formulations, and in combination with dipyridamol. Eur J Clin Pharmacol 22, 309-314.