The Dog as a Second Species for Toxicology Testing Provides Value to Drug Development.

The objective of the pharmaceutical industry is to develop new drugs that are safe for human use. In many cases, the accepted approach codified in guidance from regulatory authorities to assess the nonclinical safety profile of potential pharmaceuticals is to perform toxicity testing in two species. However, the use of a second species to establish the safety of new pharmaceuticals has been the subject of much scrutiny in recent years and the industry has been repeatedly challenged to reduce, refine, or replace some or all of the animals used to establish the safety of these pharmaceutical candidates. Specifically, the value of the dog in this testing paradigm has been questioned. Publications reviewing available data for marketed drugs suggest that for many drugs, the dog does not identify unique toxicities critical to human safety. The weakness of this approach, however, is that many of the cases where the dog (or any other species) has the greatest impact on drug development are cases for which development decisions based on safety concerns are not shared publicly. The European Federation of Pharmaceutical Industries and Associations (EFPIA) Preclinical Development Expert Group (PDEG) decided to share case studies collected from its membership and the literature to illustrate the value of the dog in drug development decision-making and clinical monitoring practices to protect the safety of trial subjects.

Integrated preclinical photosafety testing strategy for systemically applied pharmaceuticals.

Phototoxic properties of systemically applied pharmaceuticals may be the cause of serious adverse drug reactions. Therefore, a reliable preclinical photosafety assessment strategy, combining in vitro and in vivo approaches in a quantitative manner, is important and has not been described so far. Here, we report the establishment of an optimized modified murine local lymph node assay (LLNA), adapted for phototoxicity assessment of systemically applied compounds, as well as the test results for 34 drug candidates in this in vivo photo-LLNA. The drug candidates were selected based on their ability to absorb ultraviolet/visible light and the photo irritation factors (PIFs) determined in the well-established in vitro 3T3 neutral red uptake phototoxicity test. An in vivo phototoxic potential was identified for 13 of these drug candidates. The use of multiple dose levels in the described murine in vivo phototoxicity studies enabled the establishment of no- and/or lowest-observed-adverse-effect levels (NOAELs/LOAELs), also supporting human photosafety assessment. An in vitro-in vivo correlation demonstrated that a drug candidate classified as "phototoxic" in vitro is not necessarily phototoxic in vivo. However, the probability for a drug candidate to cause phototoxicity in vivo clearly correlated with the magnitude of the phototoxicity identified in vitro.