Dose range finding approach for rodent preweaning juvenile animal studies

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.

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

Human Gene Therapy ◽

10.1089/hum.2019.337 ◽

2020 ◽

Vol 31 (13-14) ◽

pp. 743-755 ◽

Cited By ~ 1

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

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Analgesic dose range finding of lornoxicam compared to diclofenac. Crossover double blind study in rheumatoid arthritis

Reumatismo ◽

10.4081/reumatismo.2002.238 ◽

2011 ◽

Vol 54 (3) ◽

Author(s):

G.P. Pasero ◽

O. Di Munno

Keyword(s):

Rheumatoid Arthritis ◽

Dose Range ◽

Blind Study ◽

Double Blind Study ◽

Double Blind ◽

Range Finding ◽

Analgesic Dose

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

Alternatives to Laboratory Animals ◽

10.1177/026119299202000105 ◽

1992 ◽

Vol 20 (1) ◽

pp. 40-49 ◽

Cited By ~ 3

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.

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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

International Journal of Toxicology ◽

10.1177/1091581817707458 ◽

2017 ◽

Vol 36 (4) ◽

pp. 287-292 ◽

Cited By ~ 1

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.

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Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies

The Journal of Rheumatology ◽

10.3899/jrheum.160164 ◽

2016 ◽

Vol 43 (9) ◽

pp. 1637-1642 ◽

Cited By ~ 10

Author(s):

Robin L. Thurmond ◽

Andrew Greenspan ◽

Waldemar Radziszewski ◽

Xie L. Xu ◽

Ye Miao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Receptor Antagonist ◽

Active Rheumatoid Arthritis ◽

Dose Range ◽

Joint Disease ◽

Double Blind ◽

Once Daily ◽

Double Blind Placebo ◽

Range Finding ◽

Phase Ii Studies

Objective.To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).Methods.In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range–finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP).Results.Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.Conclusion.Toreforant was not effective in phase IIb testing.

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