Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling

Kesisoglou, Filippos; Wu, Yunhui

doi:10.1208/s12248-008-9076-x

Cited by 17 publications

(21 citation statements)

References 20 publications

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“…It is a lipophilic compound supplied in the form of a white to off-white crystalline solid powder with pKa value of 9.7 within the pH range 2 to 12. It is considered as practically insoluble in water with low free base aqueous solubility of (3-7 μg/mL) over the physiological pH range [6][7][8]. In vivo absorption of APT through first pass metabolism leads to low bioavailability while the API is considered as having intermediate permeability across Caco2 [9,10].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

Nanaki¹,

Eleftheriou²,

Barmpalexis³

et al. 2019

Sci

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In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus® (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 °C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

Nanaki¹,

Eleftheriou²,

Barmpalexis³

et al. 2019

Sci

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show abstract

“…Since exposure is apparently solubility rate-limited, solubility scenarios chosen were (a) 0.002 mg/mL, which represents minimal formulation efforts and (b) 0.01 mg/mL assuming a 10-fold increase in solubility due to formulation optimization (28). An IR capsule and a default average particle size of 25 μm was assumed.…”

Section: Resultsmentioning

confidence: 99%

“…This case illustrates that biorelevant solubility data are crucial for accurate human predictive PK/PD modeling. Measuring relevant solubility remains a challenge (45), and more work is needed to refine the models, including precipitation kinetics (28).…”

Section: Resultsmentioning

confidence: 99%

“…We report examples for the practical projection of human PK and PK/PD concentration and effect time profiles based on preclinical PK/PD and absorption models (27,28). We illustrate modeling approaches which can be readily implemented by pharmaceutical scientists utilizing common tools such as allometric scaling (11)(12)(13)(14)29,30), the Wajima et al method (23,26), and GastroPlus™ including its PBPK, PK/ PD, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) Predictor™ software modules (31).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data

Heimbach

Lakshminarayana

et al. 2009

AAPS J

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Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and "developable" dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the "anticipation" of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for "AHD" demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via "reverse pharmacology strategies" that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.

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“…Several publications have shown the ability of dissolution to provide discriminatory data on comparing factors such as particle size and to use these data as input in PBPK type of models to forecast clinical pharmacokinetics. 18,138 However, traditional dissolution tests may not be sufficient to fully reflect the behavior of solubilizing formulation. For ASDs, the ability of the system to capture the supersaturation generated is a critical aspect of the in vitro evaluation.…”

Section: Zofenoprilmentioning

confidence: 99%

Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption

Rumondor

Dhareshwar

Kesisoglou

2016

Journal of Pharmaceutical Sciences

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Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling

Cited by 17 publications

References 20 publications

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

Evaluation of Dissolution Enhancement of Aprepitant Drug in Ternary Pharmaceutical Solid Dispersions with Soluplus® and Poloxamer 188 Prepared by Melt Mixing

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data

Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption

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