0000000000568014
AUTHOR
C. Navarro-fontestad
Computer simulations for bioequivalence trials: Selection of analyte in BCS class II and IV drugs with first-pass metabolism, two metabolic pathways and intestinal efflux transporter.
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of KM Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of t…
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 mod…
Computer simulations for bioequivalence trials: selection of analyte in BCS drugs with first-pass metabolism and two metabolic pathways.
The objective of this work is to use a computer simulation approach to define the most sensitive analyte for in vivo bioequivalence studies of all types of Biopharmaceutics Classification System (BCS) drugs undergoing first-pass hepatic metabolism with two metabolic pathways. A semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Four BCS classes (from Class I to IV) of drugs, with three possible saturation scenarios (non-saturation, saturation and saturation of only the major route of metabolism), two (high or low) dose schemes, and six types of pharmaceutical quality for the drug products were simulated. The number of investigated scenarios was 144 (4 × 3…
A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies
The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confi…
Validation of a semi-physiological model for caffeine in healthy subjects and cirrhotic patients.
The objective of this paper was to validate a previously developed semi physiological model to simulate bioequivalence trials of drug products. The aim of the model was to ascertain whether the measurement of the metabolite concentration-time profiles would provide any additional information in bioequivalence studies (Fernandez-Teruel et al., 2009a,b; Navarro-Fontestad et al., 2010). The semi-physiological model implemented in NONMEM VI was used to simulate caffeine and its main metabolite plasma levels using caffeine parameters from bibliography. Data from 3 bioequivalence studies in healthy subjects at 3 different doses (100, 175 and 400mg of caffeine) and one study in cirrhotic patients …
Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: linear kinetics (I).
Modeling and simulation approaches are useful tools to assess the potential outcome of different scenarios in bioequivalence studies. The aim of this study is to propose a new and improved semi-physiological model for bioequivalence trial simulations and apply it for all BCS (Biopharmaceutic Classification System) drug classes with non-saturated first-pass hepatic metabolism. The semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Parent drug and metabolite levels for both reference and test were simulated. Eight types of drugs (with high or low permeability and high or low solubility (class I to IV) and high or low intrinsic clearance) were considered in …