title: Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid.
abstract: The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations.
authors: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors: Ana
authors: A
authors: Cuesta-Gragera
authors: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors: Carmen
authors: C
authors: Navarro-Fontestad
authors: Department of Engineering, Pharmacy Section, Miguel Hernández University, Carretera Alicante Valencia km 87, 03550 San Juan de Alicante, Alicante, Spain.
authors: Victor
authors: V
authors: Mangas-Sanjuan
authors: Department of Engineering, Pharmacy Section, Miguel Hernández University, Carretera Alicante Valencia km 87, 03550 San Juan de Alicante, Alicante, Spain.
authors: Isabel
authors: I
authors: González-Álvarez
authors: Pharmacokinetics Service, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products (AEMPS), Campezo 1, 28022 Madrid, Spain.
authors: Alfredo
authors: A
authors: García-Arieta
authors: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31008 Pamplona, Navarra, Spain.
authors: Iñaki F
authors: IF
authors: Trocóniz
authors: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors: Vicente G
authors: VG
authors: Casabó
authors: Department of Engineering, Pharmacy Section, Miguel Hernández University, Carretera Alicante Valencia km 87, 03550 San Juan de Alicante, Alicante, Spain. Electronic address: mbermejo@goumh.umh.es.
authors: Marival
authors: M
authors: Bermejo
mesh_terms: D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001241:Aspirin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D054316:Biomarkers, Pharmacological / Q000097:blood; D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D065546:Drug Liberation; D006626:Hippurates / Q000097:blood / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010601:Pharmacology, Clinical / Q000379:methods*; D020156:Salicylic Acid / Q000097:blood / Q000378:metabolism; D012984:Software; D013810:Therapeutic Equivalency; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054316:Biomarkers, Pharmacological; D006626:Hippurates; C000693:salicylurate; D020156:Salicylic Acid; D001241:Aspirin
keywords: Acetylsalicylic acid; Analyte; Bioequivalence; First-pass metabolism; Simulation