Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

Kesisoglou, Filippos; Chung, John; Asperen, Judith van; Heimbach, Tycho

doi:10.1016/j.xphs.2015.11.034

Cited by 59 publications

(35 citation statements)

References 33 publications

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“…The final knowledgebase included 15 documents (13 peerreviewed publications [14][15][16][17][18][19][20][21][22][23][24][25][26] and 2 FDA reviews 27,28 ), consisting of 27 compounds, 36 PBPK models, and 48 food effect simulation cases. Of the 27 drugs, there were 22 bases, 2 acids, 2 ampholytes, and 1 neutral.…”

Section: Summary Of Basic Information Of the Final Knowledgebasementioning

confidence: 99%

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

Zhao

Pan

et al. 2017

CPT Pharmacom & Syst Pharma

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A comprehensive search in literature and published US Food and Drug Administration reviews was conducted to assess whether physiologically based pharmacokinetic (PBPK) modeling could be prospectively used to predict clinical food effect on oral drug absorption. Among the 48 resulted food effect predictions, ∼50% were predicted within 1.25‐fold of observed, and 75% within 2‐fold. Dissolution rate and precipitation time were commonly optimized parameters when PBPK modeling was not able to capture the food effect. The current work presents a knowledgebase for documenting PBPK experience to predict food effect.

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Section: Summary Of Basic Information Of the Final Knowledgebasementioning

confidence: 99%

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

Zhao

Pan

et al. 2017

CPT Pharmacom & Syst Pharma

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“…Application of such models can significantly enhance formulation and process development and the assessment of biopharmaceutics risk factors. The use of this type of physiologically based pharmacokinetic (PBPK) model has been a subject of several recent publications (27,28).…”

Section: Clinically Relevant Specification Roadmapmentioning

confidence: 99%

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

Hermans

Abend

Kesisoglou

et al. 2017

AAPS J

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Abstract.This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post-approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed.KEY WORDS: BCS; biowaivers; clinically relevant dissolution specifications; PBPK modeling; SUPAC.This article was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader research and development community. PURPOSEThe purpose of this paper is to describe a roadmap for the development and leverage of clinically relevant dissolution specifications (CRS) for immediate release oral solid dosage forms of non-narrow therapeutic window drugs. There are three objectives for presenting this roadmap: (1) to describe multiple approaches for establishing clinical relevance for dissolution methodology, (2) to outline how to leverage clinically relevant dissolution methodology and specifications for the confirmation of the final drug product quality, and (3) to suggest recommendations on supporting scale-up and post-approval changes using the established CRS.Historically, dissolution specifications have been set by controlling the formulation and process within prec...

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“…Los efectos de solvente sobre las estructuras se consideraron en todos los cálculos mediante el modelo de solvente del continuo polarizable, implementados en el paquete computacional GAUSSIAN 03 (Trucks y otros 80 autores). Las propiedades de los fármacos tipo ADME (absorción, distribución, metabolismo y excreción) se estimaron con el programa MedChem Designer v. 3.1.0.30 (Kesisoglou et al, 2016). Adicionalmente, los descriptores topológicos y geométricos se generaron mediante MarvinSketch (Evans y Moore, 2011).…”

Section: Metodologíaunclassified

Modelado de las Relaciones Cuantitativas Estructura-Actividad (QSAR) de los Derivados 5-(Nitroheteroaril) -1,3,4-tiadiazol con Actividad Leishmanicida

Robles

Figueredo

2017

Inf. tecnol.

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ResumenEn este trabajo se analizaron las relaciones de estructura-actividad para un grupo de derivados del compuesto 5-(nitroheteroaril)-1,3,4-tiadiazol con actividad leishmanicida frente a Leishmania major. Los descriptores utilizados para construir los modelos de regresión fueron de naturaleza topológica y electrónica, derivados de la teoría del funcional de la densidad. Los modelos QSAR obtenidos presentaron buena calidad estadística (R 2 >0,6 y Q 2 >0,5), y se validaron mediante la técnica de validación cruzada dejando uno fuera. Los modelos se mejoraron utilizando la técnica jackknife. La validación externa de los modelos indicó buena capacidad predictiva. Por otra parte, los descriptores usados en los modelos indican que el aumento creciente del momento dipolar y el índice de hidrofobicidad disminuyen la actividad biológica. Además, el poder electrofílico aumenta la actividad de los derivados. El análisis de reactividad mostró que el grupo nitro presente en estos compuestos es la parte más reactiva de los derivados. Palabras clave: QSAR; leishmaniasis; poder electrófilo; hidrofobicidad; grupo nitro Modeling Quantitative Structure-Activity Relationship (QSAR) of Derivatives 5-(5-Nitroheteroaryl)-1,3,4-thiadiazols with Leishmanicidal Activity AbstractIn the present work a structure-activity relationship (QSAR) analysis for some derivatives of 5-(5-nitroheteroaryl)-1,3,4-thiadiazols with activity against protozoan Leishmania major; the main cause of leishmaniasis disease was performed. The set of descriptors used to build regression models were from electronic and topological nature, and derived from the density functional theory. QSAR models built enjoy a good statistical quality (R 2 > 0,6 and Q 2 > 0,5) and were validated by cross-validation technique. Moreover, parameters were improved by using the jackknife regression technique. External validation of models showed a good predictive quality. We found that descriptors from the models indicate the increasing of dipole moment and hydrophobicity index tends to worsen the biological activity. Also, electrophilic power improves the effectiveness of 5-(5-nitroheteroaryl)-1,3,4-thiadiazols.The analysis showed that the reactivity nitro group present in these compounds is the most reactive derivative of such part.

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Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

Cited by 59 publications

References 33 publications

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

Predictive Performance of Physiologically Based Pharmacokinetic Models for the Effect of Food on Oral Drug Absorption: Current Status

Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms

Modelado de las Relaciones Cuantitativas Estructura-Actividad (QSAR) de los Derivados 5-(Nitroheteroaril) -1,3,4-tiadiazol con Actividad Leishmanicida

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