Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: Early liability assessment during lead optimization

Saxena, Ajay K.; Shah, Devang; Padmanabhan, Shweta; Gautam, Shashyendra Singh; Chowan, Gajendra; Mandlekar, Sandhya; Desikan, Sridhar

doi:10.1016/j.ejps.2015.05.006

Cited by 20 publications

(22 citation statements)

References 25 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to their use for toxicology (Forti et al, 2010(Forti et al, , 2011 and drug transport studies, 16HBE 14o-and Calu-3 cell lines are frequently used for analysis of pathways involved in barrier function in response to environmental agents including allergens (Vinhas et al, 2011;Wan et al, 2001), particulates (Banga et al, 2012), cigarette smoke (Heijink et al, 2012) or viral infections (Harcourt et al, 2011;Rezaee et al, 2011). The other frequently used bronchial epithelial cell line, BEAS2B (Reddel et al, 1988), is not of value for transport studies as it fails to form an appreciable barrier (Forbes and Ehrhardt, 2005). However, this cell line is routinely used for mechanistic studies, responding to cytokines, danger signals and pathogens (Edwards et al, 2006;Hara et al, 2012).…”

Section: Cfdeo-/6rep-cftrmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

View full text Add to dashboard Cite

SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

show abstract

Section: Cfdeo-/6rep-cftrmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

View full text Add to dashboard Cite

show abstract

“…To evaluate the potential impact of elevated gastric pH on clinical PK, an absorption model was constructed using the physiochemical properties of lanabecestat with observed clinical PK results. GastroPlus (Simulations Plus, Inc., Lancaster, California) is a mechanistically based simulation software package that simulates absorption and pharmacokinetics in humans and animals and has been used to model the absorption behavior of drugs . A preliminary absorption model was constructed using a combination of in silico and in vitro physiochemical properties.…”

Section: Methodsmentioning

confidence: 99%

“…Gastro-Plus (Simulations Plus, Inc., Lancaster, California) is a mechanistically based simulation software package that simulates absorption and pharmacokinetics in humans and animals and has been used to model the absorption behavior of drugs. [28][29][30]…”

Section: Pk Modeling To Assess Changes In Bioavailability With Differmentioning

confidence: 99%

Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics

Monk

Daga

et al. 2018

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single‐center, open‐label, randomized, 3‐period crossover study involved healthy male and nonfertile female subjects aged 18–55 years (NCT02039180). Subjects received a single 50‐mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0–∞ (area under the plasma drug concentration–time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1.052 (90% confidence interval [CI], 1.001–1.106); tablet B, 1.040 (0.989–1.093). These 90%CIs for geometric mean ratios are within accepted standard bioequivalence boundaries for all other pharmacokinetic (PK) parameters for both lanabecestat and metabolite (AZ13569724). All 3 formulations had similar plasma lanabecestat concentration–time profiles. Six adverse events were reported by 6 subjects (37.5%, all mild). GastroPlus modeling predicted a negligible impact of gastric pH changes on systemic PK (up to pH 7.4). Both tablet formulations fall within standard accepted bioequivalence criteria versus the oral solution. A single 50‐mg lanabecestat dose was well tolerated as a solution or tablet formulation in this population.

show abstract

“…While, the rats in Group C were pretreated with cycloheximide (3 mg/kg; i.p; 0.6 mg/mL solution in normal saline) one hour prior to the administration of ATZ-SP-IM [40]. Further, rats in Group D and E were pretreated with famotidine (25 mg/kg; per oral; 5 mL/kg in 100mM phosphate buffer, pH 6.5) one hour prior to the administration of ATZ-SP-IM and ATZ suspension [12]. All the animals received a dose equivalent to 7 mg/kg of atazanavir.…”

Section: In-vivo Pharmacokinetic Studymentioning

confidence: 99%

In-Silico Assisted Development of Supersaturable Preconcentrated Isotropic Mixture of Atazanavir for Augmenting Biopharmaceutical Performance in Presence of H2-Receptor Antagonist

Sethi

Rana

2022

Preprint

View full text Add to dashboard Cite

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1) has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization and evaluation of HPMC-AS based supersaturable preconcentrate isotropic mixture (SP-IM) containing long chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing Corn Oil, Oleic acid, Tween 80 and Propylene Glycol, evaluating CQAs like particle size, PDI, self-emulsification time, % transmittance and drug content. In-silico analysis and in-vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In-vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025N HCl and pH 6.8 over pure drug. Ex-vivo permeation and in-vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

show abstract

Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: Early liability assessment during lead optimization

Cited by 20 publications

References 25 publications

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics

In-Silico Assisted Development of Supersaturable Preconcentrated Isotropic Mixture of Atazanavir for Augmenting Biopharmaceutical Performance in Presence of H2-Receptor Antagonist

Contact Info

Product

Resources

About