Postnatal Hepatobiliary and Gastrointestinal Systems Development and Impact on ADME

2021 ◽  
pp. 019262332110437
Author(s):  
Wendy G. Halpern ◽  
April Kluever ◽  
Armando R. Irizarry Rovira
Keyword(s):  
Drug Disposition ◽  
Developmental Toxicity ◽  
Dose Range ◽  
Systems Development ◽  
Intestinal Microbiome ◽  
Metabolizing Enzymes ◽  
Functional Changes ◽  
Range Finding ◽  
Enteral Feedings ◽  
Species Specific

Toxicity can result from variable target organ sensitivity and exposure based on postnatal development. Changes in the gastrointestinal tract (GIT) in neonates are driven by initial enteral feedings. These are important for nutrient uptake as well as drug disposition and include motility, expansion of enzyme and transporter function, permeability, intestinal microbiome, and species-specific maturation. Some aspects of GIT function do not mature until driven by increased dietary complexity. As with the GIT, postnatal hepatic maturation in the rat includes a variety of anatomic and functional changes that include refinements in the activities or expression of drug transporters and drug-metabolizing enzymes. These changes may impact rodent pharmacokinetics, nonclinical toxicity profiles, and estimation of safe pediatric doses. Pilot or dose range finding studies can help characterize and mitigate toxicity related to drug disposition, especially in juvenile rodents. Interpretation of developmental toxicity requires knowledge of developing systems in humans and nonclinical models.

Dried Blood Spot Analysis of Donepezil in Support of a GLP 3-month Dose-Range Finding Study in Rats

2012 ◽  
Vol 31 (4) ◽  
pp. 337-347 ◽  
Author(s):  
Susan R. Meier-Davis ◽  
Min Meng ◽  
Weiwei Yuan ◽  
Lisa Diehl ◽  
Fatima M. Arjmand ◽  
...  
Keyword(s):  
Dose Range ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Dried Blood Spot ◽  
Topical Formulation ◽  
Carcinogenicity Study ◽  
Range Finding ◽  
Donepezil Hydrochloride ◽  
Blood Spot

Donepezil hydrochloride is a reversible acetyl cholinesterase inhibitor approved for Alzheimer disease treatment. As an alternate therapy, a donepezil hydrochloride transdermal patch is in development. Recommended nonclinical safety studies include a 3-month Good Laboratory Practice (GLP) dose-range finding (DRF) study prior to conducting the 2-year dermal carcinogenicity study in rats. Demonstration of systemic exposure is necessary to interpret the in vivo data. Previous nonclinical reports supporting oral dosing have utilized liquid chromatography tandem mass spectrometry (LC/MS/MS) to quantify donepezil concentrations in plasma. Smaller species with limited blood volumes do not allow serial sampling to derive the full pharmacokinetic profile from a single animal. Therefore, the option of another analytical method requiring decreased sample volumes is desirable as it would decrease the required number of animals while obtaining the complete profile. The dried blood spot (DBS) technique allows drug level measurement from a few microliters; however, the method is still not widely utilized in GLP studies. Because donepezil plasma levels are known by the oral route, DBS was used to bridge the previous oral data and to support a 13-week GLP DRF study for repeated topical application in rats, comparing oral administration with 4 topical formulations. The DBS method was validated and demonstrated robustness and reproducibility for application to the DRF study. The assay results were comparable to a previously reported plasma LC/MS/MS assay-derived pharmacokinetic profile and provided justification for selection of the topical formulation and dose levels for the subsequent dermal carcinogenicity study.

Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

2006 ◽  
Vol 291 (2) ◽  
pp. H496-H506 ◽  
Author(s):  
Martina Krüger ◽  
Thomas Kohl ◽  
Wolfgang A. Linke
Keyword(s):  
Guinea Pig ◽  
Heart Development ◽  
Troponin I ◽  
Collagen Matrix ◽  
Passive Stiffness ◽  
Adult Rats ◽  
Functional Changes ◽  
Fetal Rat ◽  
Isoform Switching ◽  
Species Specific

The giant protein titin, a major contributor to myocardial mechanics, is expressed in two main cardiac isoforms: stiff N2B (3.0 MDa) and more compliant N2BA (>3.2 MDa). Fetal hearts of mice, rats, and pigs express a unique N2BA isoform (∼3.7 MDa) but no N2B. Around birth the fetal N2BA titin is replaced by smaller-size N2BA isoforms and N2B, which predominates in adult hearts, stiffening their sarcomeres. Here we show that perinatal titin-isoform switching and corresponding passive stiffness (STp) changes do not occur in the hearts of guinea pig and sheep. In these species the shift toward “adult” proportions of N2B isoform is almost completed by midgestation. The relative contributions of titin and collagen to STp were estimated in force measurements on skinned cardiac muscle strips by selective titin proteolysis, leaving the collagen matrix unaffected. Titin-based STp contributed between 42% and 58% to total STp in late-fetal and adult sheep/guinea pigs and adult rats. However, only ∼20% of total STp was titin based in late-fetal rat. Titin-borne passive tension and the proportion of titin-based STp generally scaled with the N2B isoform percentage. The titin isoform transitions were correlated to a switch in troponin-I (TnI) isoform expression. In rats, fetal slow skeletal TnI (ssTnI) was replaced by adult carciac TnI (cTnI) shortly after birth, thereby reducing the Ca2+ sensitivity of force development. In contrast, guinea pig and sheep coexpressed ssTnI and cTnI in fetal hearts, and skinned fibers from guinea pig showed almost no perinatal shift in Ca2+ sensitivity. We conclude that TnI-isoform and titin-isoform switching and corresponding functional changes during heart development are not initiated by birth but are genetically programmed, species-specific regulated events.

scholarly journals Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy

2020 ◽  
Vol 31 (13-14) ◽  
pp. 743-755 ◽  
Author(s):  
Chunjuan Song ◽  
Valérie L. Dufour ◽  
Artur V. Cideciyan ◽  
Guo-Jie Ye ◽  
Malgorzata Swider ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Dose Range ◽  
Canine Model ◽  
Range Finding

scholarly journals Prediction of Biopharmaceutical Drug Disposition Classification System (BDDCS) by Structural Parameters

2019 ◽  
Vol 22 ◽  
pp. 247-269 ◽  
Author(s):  
Yeganeh Golfar ◽  
Ali Shayanfar
Keyword(s):  
Classification System ◽  
Drug Disposition ◽  
Structural Parameters ◽  
Log P ◽  
Metabolizing Enzymes ◽  
Acceptable Accuracy ◽  
Water Partition Coefficient ◽  
Pharmacokinetic Properties ◽  
Solvation Parameters ◽  
External Test

Modeling of physicochemical and pharmacokinetic properties is important for the prediction and mechanism characterization in drug discovery and development. Biopharmaceutics Drug Disposition Classification System (BDDCS) is a four-class system based on solubility and metabolism. This system is employed to delineate the role of transporters in pharmacokinetics and their interaction with metabolizing enzymes. It further anticipates drug disposition and potential drug-drug interactions in the liver and intestine. According to BDDCS, drugs are classified into four groups in terms of the extent of metabolism and solubility (high and low). In this study, structural parameters of drugs were used to develop classification-based models for the prediction of BDDCS class. Reported BDDCS data of drugs were collected from the literature, and structural descriptors (Abraham solvation parameters and octanol–water partition coefficient (log P)) were calculated by ACD/Labs software. Data were divided into training and test sets. Classification-based models were then used to predict the class of each drug in BDDCS system using structural parameters and the validity of the established models was evaluated by an external test set. The results of this study showed that log P and Abraham solvation parameters are able to predict the class of solubility and metabolism in BDDCS system with good accuracy. Based on the developed methods for prediction solubility and metabolism class, BDDCS could be predicted in the correct with an acceptable accuracy. Structural properties of drugs, i.e. logP and Abraham solvation parameters (polarizability, hydrogen bonding acidity and basicity), are capable of estimating the class of solubility and metabolism with an acceptable accuracy.

Two Procedures for the Prediction of Acute Toxicity (LD50) from Cytotoxicity Data

1992 ◽  
Vol 20 (1) ◽  
pp. 40-49 ◽  
Author(s):  
Willi Halle ◽  
Horst Spielmann
Keyword(s):  
Linear Regression ◽  
Acute Toxicity ◽  
Correlation Coefficient ◽  
Mammalian Cell ◽  
Wide Spectrum ◽  
Dose Range ◽  
Linear Regression Analysis ◽  
Range Finding ◽  
Mammalian Cell Lines ◽  
Ic50 Values

Single linear regression analysis was used to characterise the relationship between cytotoxicity in a variety of mammalian cell culture systems and acute oral toxicity (LD50) in experimental animals. The following results were obtained. Firstly, in a cytotoxicity assay using the calf aortic endothelial cell line BKEz-7, IC50 values determined for 44 chemicals in culture showed significant correlation with the oral LD50 values for rat and mouse (computed correlation coefficient r=0.546). After eliminating three chemicals that were characterised by extreme lethality indices (LI = IC50/LD50), the correlation coefficient of the remaining 41 chemicals increased to a value of r=0.728. By using the linear regression model for these 41 chemicals, the oral LD50 for rat and mouse can be predicted correctly from the IC50 values for 83% of substances from a variety of chemical substance classes within a range of approximately one order of magnitude of dosage unit of LD50 for rat and mouse. Secondly, the mean IC50 values (IC50x¯) determined as the geometrical mean of two or more IC50 values per substance, which were generated in a wide spectrum of mammalian cell lines and collected in a “Registry of Cytotoxicity” (RC), gave similar results (r=0.644). Likewise, with the aid of this method, the oral LD50 for rat and mouse can be predicted for 74% of non-selected chemicals from structurally-different classes in the same dosage range, e.g., 1–25 millimoles per kg body weight. The prediction of LD50 values from in vitro cytotoxicity data may permit the calculation of a more precise dose range-finding and offers a new way for reducing the number of animals in acute toxicity testing.

scholarly journals Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

2017 ◽  
Vol 36 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Madhav G. Paranjpe ◽  
Jessica Belich ◽  
Tom J. Vidmar ◽  
Reem H. Elbekai ◽  
Marie McKeon ◽  
...  
Keyword(s):  
Selection Process ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Dose Selection ◽  
Range Finding ◽  
Body Weights ◽  
Vehicle Test ◽  
High Doses ◽  
Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

Sign in / Sign up

Export Citation Format

Share Document