<i>In vitro</i>and<i>in vivo</i>testing methods for respiratory drug delivery

Agu, Remigius U.; Ugwoke, Michael Ikechukwu

doi:10.1517/17425247.2011.543896

Cited by 41 publications

(32 citation statements)

References 85 publications

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“…A slow dissolution process in the pulmonary fluids in combination with a fast absorption process of the dissolved drug to the plasma might then appear as a single absorption process. Based on clinical data alone, it might not be possible to differentiate between the dissolution and the absorption process, and to this date including information from in vitro dissolution assays may not be trivial as no versatile in vitro dissolution assay representing pulmonary dissolution processes has been established (95)(96)(97). Another physiologically plausible explanation for only a single absorption process might be relevant for insulin.…”

Section: Empirical Pk Models Based On Inhalation and Additional Datamentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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Abstract. During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

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Section: Empirical Pk Models Based On Inhalation and Additional Datamentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

View full text Add to dashboard Cite

show abstract

“…Unfortunately, progress towards the clinic has been hindered because in vitro results generally do not correlate well with in vivo data 1–3 . This has been particularly true for RNA interference therapeutics (RNAi) 4 .…”

Section: Introductionmentioning

confidence: 99%

Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

et al. 2014

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One of the most significant challenges in the development of clinically-viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. To this end, we synthesized 1400 degradable lipidoids and evaluated their transfection ability and structure function activity. Here we show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations upon IV administration to mice (siRNA EC50 values as low as 0.01 mg/kg). Surprisingly, we identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.

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“…Despite their extensive use in toxicology 52 and therapeutic studies 1 relatively few studies have simulated airflow 32 and particle deposition in the rat lung. In a recent study, CFD and MRI steady flow measurements agreed well in the conducting airways.…”

Section: Introductionmentioning

confidence: 99%

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

et al. 2013

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Image-based in-silico modeling tools provide detailed velocity and particle deposition data. However, care must be taken when prescribing boundary conditions to model lung physiology in health or disease, such as in emphysema. In this study, the respiratory resistance and compliance were obtained by solving an inverse problem; a 0D global model based on healthy and emphysematous rat experimental data. Multi-scale CFD simulations were performed by solving the 3D Navier Stokes equations in an MRI-derived rat geometry coupled to a 0D model. Particles with 0.95 μm diameter were tracked and their distribution in the lung was assessed. Seven 3D-0D simulations were performed: healthy, homogeneous, and five heterogeneous emphysema cases. Compliance (C) was significantly higher (p = 0.04) in the emphysematous rats (C=0.37±0.14cm3cmH2O) compared to the healthy rats (C=0.25±0.04cm3cmH2O), while the resistance remained unchanged (p=0.83). There were increases in airflow, particle deposition in the 3D model, and particle delivery to the diseased regions for the heterogeneous cases compared to the homogeneous cases. The results highlight the importance of multi-scale numerical simulations to study airflow and particle distribution in healthy and diseased lungs. The effect of particle size and gravity were studied. Once available, these in-silico predictions may be compared to experimental deposition data.

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In vitroandin vivotesting methods for respiratory drug delivery

Cited by 41 publications

References 85 publications

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

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