Browsing by Author "Aceituno, Alexis"

Now showing 1 - 4 of 4
  • No Thumbnail Available
    Item
    "Development of Fixed Dose Combination Products" Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy
    (2019) Hens, Bart; Corsetti, Maura; Bermejo, Marival; Lobenberg, Raimar; Gonzalez, Pablo M.; Mitra, Amitava; Desai, Divyakant; Chilukuri, Dakshina Murthy; Aceituno, Alexis
    The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions.
  • Thumbnail Image
    Item
    Exploring Experimental and Statistical Approaches to Control Oversensitivity of In Vitro Permeability to Excipient Effects
    (MDPI, 2025) García Alcalde, Mauricio Andrés; Aceituno, Alexis; Díaz Santana, Nicole Belén; Tapia Rivera, Eduardo Moisés; Contreras Valverde, Danae Valentina; López Lagos, Constanza Beatriz Estefanía; Sánchez, Virginia; González, Pablo M.
    Background/Objectives: The static in vitro permeability assay based on cell monolayers has been widely used in the pharmaceutical industry and recognized by regulatory agencies as a surrogate method for BCS classification. However, the application of such an experiment to study the effects of formulations is limited by the oversensitivity to the excipient effect on drug permeability. In this article, we studied the effects of common excipients on the permeability of moderately and poorly absorbed model compounds across cell monolayers, using two approaches to control said oversensitivity. Methods: Drug permeability across MDCK-wt was assessed in the absence (control) or presence (treatment) of excipients, using minoxidil as a high-permeability marker. The effects of excipients were parameterized as a permeability ratio (PR = treatment/control) without or with normalization (nPR) by minoxidil permeability. Metrics were compared by either ANOVA (p < 0.01) or confidence intervals (CI90, as per bioequivalence metrics) to identify excipient effects. Results: Acyclovir and hydrochlorothiazide showed the highest and lowest number of interactions, respectively. The most impactful excipients were sodium lauryl sulfate, microcrystalline cellulose, and sodium starch glycolate. Unexpectedly, nPR increased the number of excipient effects across model drugs (19 vs. 21). Alternatively, the CI90 approach was more sensitive than ANOVA in identifying excipient effects (41 vs. 32). Conclusions: Minoxidil was not able to control the anticipated oversensitivity of cell-based permeability experiments. Meanwhile, ANOVA was overall able to reduce oversensitivity to excipient effects on drug permeability compared to CI90. Nonetheless, there might be a niche for CI90 analysis when comparing the performance of two formulations on the permeability of moderately and poorly absorbed drugs.
  • No Thumbnail Available
    Item
    Modeling and Simulations in Latin-American Generic Markets: Perspectives from Chilean Local Industry, Regulatory Agency, and Academia
    (AMER CHEMICAL SOC, 2024) Garcia, Mauricio A.; Paulos, Claudio; Vinales, Manuel Ibarra; Michelet, Robin; Cabrera-Pérez, Miguel Ángel; Aceituno, Alexis; Bone, Michelle; Ibacache Figueroa, Mauricio Enrique; Cortínez Fernández, Luis Ignacio; Guzman, Marcelo
    In the last 20 years, modeling and simulations (M&S) have gained increased attention in pharmaceutical sciences. International industry and world-reference agencies have used M&S to make cost-efficient decisions through the model-informed drug development (MIDD) framework. Modeling tools include biopredictive dissolution models, physiologically based pharmacokinetic models (PBPK), biopharmaceutic models (PBBM), and virtual bioequivalence, among many others. Regulatorily, health agencies are becoming more and more open to accept the use of M&S to support regulatory applications, including setting dissolution specifications, quality-by-design (QbD), postapproval changes (SUPAC), etc. Nonetheless, the potential of M&S has been only barely explored in Latin America (Latam) across different actors: industry, regulatory agencies, and even academia. In this manuscript, we discuss the challenges and opportunities for implementing M&S approaches in Latam. Perspectives of regional experts were shared in a workshop. Attendance (professionals from industry, regulator, academia, and clinicians) also shared their views via survey. The rational development of bioequivalent generics was considered the main opportunity for M&S in regional market, particularly the use of PBPK and PBBM. Nonetheless, a critical mass of modeling scientists is needed before Latin American industry and regulators can actually benefit from M&S. Collaborations (e.g., Academia-Industry and Academia-Regulatory) may be a path to develop applied research projects and train the future modelers. Reaching that critical mass, scientists from industry may apply modeling across generic drug development process and life cycle, while regulatory scientists may issue guidelines in local language to support regional industry. Only at that stage could the full potential of MIDD be reached in Latin American generic markets.
  • Thumbnail Image
    Item
    Novel analytical solutions for convolution in compartmental pharmacokinetic models and application to non-bioequivalent formulations
    (Elsevier B.V., 2024) García Alcalde, Mauricio Andrés; Gonzalez Pablo M.; Aceituno, Alexis; Al-Gousous, Josef
    © 2024 The AuthorsDeconvolution and convolution are powerful tools that allow decomposition and reconstruction, respectively, of plasma versus time profiles from input and impulse functions. While deconvolution have commonly used compartmental approaches (e.g., Wagner-Nelson or Loo-Riegelman), convolution most typically used the convolution integral which can be solved with numerical methods. In 2005, an analytical solution for one-compartment pharmacokinetic was proposed and has been widely used ever since. However, to the best of our knowledge, analytical solutions for drugs distributed in more than one compartment have not been reported yet. In this paper, analytical solutions for compartmental convolution from both original and exact Loo-Riegelman approaches were developed and evaluated for different scenarios. While convolution from original approach was slightly more precise than that from the exact Loo-Riegelman, both methods were extremely accurate for reconstruction of plasma profiles after respective deconvolutions. Nonetheless, convolution from exact Loo-Riegelman was easier to interpret and to be manipulated mathematically. In fact, convolution solutions for three and more compartments can be easily written with this approach. Finally, our convolution analytical solution was applied to predict the failure in bioequivalence for levonorgestrel, demonstrating that equations in this paper may be useful tools for pharmaceutical scientists.