Toxicity study in juvenile rats with the α4β2 nicotinic acetylcholine receptor partial agonist CP-601,927

Abstract

Treatment-related findings included the death of 2 males receiving 3 mg/kg CP-601,927, and transient reductions in body weight for both males and females during the third week of dosing which quickly recovered to control levels. The only treatment-related alteration in behavior was decreased motor activity, which occurred only in females at the highest dose tested. CP-601,927 had no effect on acoustic startle response, learning and memory, sexual maturation, reproductive capacity, or general toxicity endpoints.

Value of juvenile animal studies

“…A recent review of juvenile animal toxicity study designs to support pediatric drug development illustrated examples of both design approaches (Cappon et al, 2009). Examples of these different types of approaches have recently been published as well (Bowman et al, 2011; Campion et al, 2011; Cappon et al, 2011; Wise et al, 2011).…”

Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors

“…Attachment of a trifluoromethyl group to the C-4 position of benzazapine 24 gives 16 and CP-601932 ( 25 ) (Figure ). Compound 16 is a selective α4β2-nAChR partial agonist with weaker activity at the α3β4-nAChRs ( K i,α4β2 = 1.2 nM vs K i,α3β4 = 102 nM), whereas its enantiomer, 25 , shows similar affinities at both receptor subtypes, with K i values of 21 nM and lower affinities for the α6- and α7-nAChR subtypes ( K i > 300 nM). , Compound 16 decreased the time spent immobile in the FST at 0.75, 1, and 1.5 mg/kg, whereas no significant effect was found in the TST at the same doses . Moreover, compound 16 was found to be relatively safe and well-tolerated in phase 1 single- and multiple-dose studies, but it failed to show a statistically significant change on the primary efficacy scale in favor of the drug when used in the augmentation of antidepressant therapy in major depression in a phase 2 clinical study…”

Nonclinical support of pediatric drug development in a global context: an industry perspective

“…Although the targeted study design has been accepted by PDCO (Bowman et al, 2011), there is some concern that the regulatory openness to considering this approach is fading, and the favored approach of regulatory agencies is to require a modified general toxicity screening study (see Text Box 2 for communication from regulatory authorities in the US and EU requesting a modified general toxicity screening study in juvenile animals). Although this type of study design may be appropriate in some circumstances (for example see (Campion et al, 2011)), the default use of this study design is clearly not the intent of the US and EU regulatory guidance documents.…”