From Bench to Humans: Formulation Development of a Poorly Water Soluble Drug to Mitigate Food Effect

Pandey, Preetanshu; Hamey, Rhye; Bindra, Dilbir S.; Huang, Zhanwen; Mathias, Neil; Eley, Timothy; Crison, John R.; Yan, Brian; Perrone, Robert; Vemavarapu, Chandra

doi:10.1208/s12249-013-0069-4

Cited by 30 publications

(13 citation statements)

References 27 publications

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“…Overall, BMS-C's FE mechanism was driven by solubilization in high-fat meal, aided further by the delayed fed-state gastric emptying that prolongs the window of absorption (36). Using this knowledge, FE mitigation strategies such as the inclusion of surfactants and lipid formulation additives were found to show improved bioavailability in the fasted state (38).…”

Section: Case Studies On Fe Mechanismsmentioning

confidence: 99%

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Mathias

Yang

Vig

et al. 2015

AAPS J

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Abstract. In vitro and in vivo experimental models are frequently used to assess a new chemical entity's (NCE) biopharmaceutical performance risk for food effect (FE) in humans. Their ability to predict human FE hinges on replicating key features of clinical FE studies and building an in vitro-in vivo relationship (IVIVR). In this study, 22 compounds that span a wide range of physicochemical properties, Biopharmaceutics Classification System (BCS) classes, and food sensitivity were evaluated for biorelevant dissolution in fasted-and fed-state intestinal media and the dog fed/fasted-state pharmacokinetic model. Using the area under the curve (AUC) as a performance measure, the ratio of the fed-to-fasted AUC (FE ratio) was used to correlate each experimental model to FE ratio in humans. A linear correlation was observed for the in vitro dissolution-human IVIVR (R 2 =0.66, % mean square error 20.7%). Similarly, the dog FE ratio correlated linearly with the FE ratio in humans (R 2 =0.74, % mean square error 16.25%) for 15 compounds. Data points near the correlation line indicate dissolution-driven mechanism for food effect, while deviations from the correlation line shed light on unique mechanisms that can come into play such as GI physiology or unusual physicochemical properties. In summary, fed/fasted dissolution studies and dog PK studies show a reasonable correlation to human FE, hence are useful tools to flag high-risk NCEs entering clinical development. Combining kinetic dissolution, dog FE model and in silico modeling one can study FE mechanism and formulation strategies to mitigate the FE risk.KEY WORDS: biorelevant dissolution; dog food effect model; food effect; in vitro-in vivo relationship.

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Section: Case Studies On Fe Mechanismsmentioning

confidence: 99%

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Mathias

Yang

Vig

et al. 2015

AAPS J

Self Cite

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“…However, adjustment of certain model parameters, enabled by the availability of in vivo animal and human data, was required for accurate prediction of plasma profiles. Additional software including IDEA™, PK-Sim ® , and STELLA employ similar frameworks (compartment-based) and have been used to predict the effect of ingested food on drug absorption [167, 170, 171]. Overall, literature reports support the promise of employing PBPK models in predicting food effect, but indicate that models currently widely employed require in vivo data to optimize model parameters for confidence in PK predictions.…”

Section: Value Of Mathematical Modeling and Existing Modeling Apprmentioning

confidence: 99%

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

Rezhdo

Speciner

Carrier

2016

Journal of Controlled Release

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The majority of newly discovered oral drugs are poorly water soluble, and co-administration with lipids has proven effective in significantly enhancing bioavailability of some compounds with low aqueous solubility. Yet, lipid-based delivery technologies have not been widely employed in commercial oral products. Lipids can impact drug transport and fate in the gastrointestinal (GI) tract through multiple mechanisms including enhancement of solubility and dissolution kinetics, enhancement of permeation through the intestinal mucosa, and triggering drug precipitation upon lipid emulsion depletion (e.g., by digestion). The effect of lipids on drug absorption is currently not quantitatively predictable, in part due to the multiple complex dynamic processes that can be impacted by lipids. Quantitative mechanistic analysis of the processes significant to lipid system function and overall impact on drug absorption can aid understanding of drug-lipid interactions in the GI tract and exploitation of such interactions to achieve optimal lipid-based drug delivery. In this review, we discuss the impact of co-delivered lipids and lipid digestion on drug dissolution, partitioning, and absorption in the context of the experimental tools and associated kinetic expressions used to study and model these processes. The potential benefit of a systems-based consideration of the concurrent multiple dynamic processes occurring upon co-dosing lipids and drugs to predict the impact of lipids on drug absorption and enable rational design of lipid-based delivery systems is presented.

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“…In vitro metabolism data Permeability estimate Preclinical species IV PK data Stability in biorelevant fluids FIH formulation characterization PSD for FIH formulation FIH, phase IIB/III Impact of changes in dissolution profile, formulation related Impact of changes in dissolution profile, process and /or stability related Impact of release rate for MR formulations 22 Impact of API PSD 22,24 Physiologically based IVIVC 31 Impact of physiological variability (e.g., stomach pH) 20,21 Food effect assessment [16][17][18] Estimate of precipitation time in vivo from clinical data Verification of understanding of oral absorption and disposition in healthy volunteers and patients PBPK-PD…”

Section: Application Of Absorption Pbpk Modeling In Pharmaceutical Dementioning

confidence: 99%

“…Food effect predictions have been relatively well documented. [14][15][16][17][18] More recently, a few publications have also focused on understanding stomach pH-related interactions. [19][20][21][22] A few literature reports have demonstrated the potential applicability of PBPK modeling to study active pharmaceutical ingredient (API) properties [22][23][24] or understand the impact of dissolution differences during manufacturing changes.…”

Section: Introductionmentioning

confidence: 99%

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

Kesisoglou¹,

Chung

Asperen

et al. 2016

Journal of Pharmaceutical Sciences

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In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions.

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From Bench to Humans: Formulation Development of a Poorly Water Soluble Drug to Mitigate Food Effect

Cited by 30 publications

References 27 publications

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Food Effect in Humans: Predicting the Risk Through In Vitro Dissolution and In Vivo Pharmacokinetic Models

Lipid-associated oral delivery: Mechanisms and analysis of oral absorption enhancement

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

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