The presence of drug in control samples during toxicokinetic investigations--a Novartis perspective.

ABSTRACT

During a submission procedure, the validity of a few dietary toxicity studies was questioned because low levels of the drug were detected among control toxicokinetic samples. Although several lines of reasoning suggested that these findings arose from ex vivo contamination, the Regulatory Authority stated that it was not possible to establish a no-effect-level in any of the studies and so the submission was withdrawn. In response, Novartis conducted a thorough review and modification of the procedures involved in the collection and analysis of toxicokinetic samples to minimize such contamination in future studies. Ongoing monitoring of contamination in toxicology studies has subsequently revealed that although it was not possible to completely eliminate the problem, the new procedures together with an increasing awareness of the issue have considerably reduced the incidence of contamination. The process of contamination and its control was also modeled in a feeding study in mice. This provided good evidence that the detection of drug in control samples in the previous studies originated from external sources and not from in vivo exposure.