Impact of dosing schedule in animal experiments on compound progression decisions.

Highlights • Inadequate dosing schedule in preclinical studies erodes therapeutic index. • This erosion can prevent potentially effective drugs from entering clinical trials. • Dosing in animals must account for species difference to allow human translation. • Improved dosing practice to produce human-relevant exposure profiles is needed. Low pipeline output is a major problem for the pharmaceutical industry. Many compounds fail to enter clinical development, owing to toxicities in animals. Using pharmacology principles, this paper argues that the often-infrequent dosing in animal experiments despite a drug's short half-life produces a large fluctuation in drug concentration, which can severely erode the therapeutic index and safety margin for the anticipated clinical dose, consequently preventing potentially effective treatments from entering human trials. Aided by computer simulations under generalised conditions, the analysis was conducted in a quantitative framework with broad relevance. The findings call for more-translatable dosing practices through closer collaboration among scientists in multiple disciplines and better regulatory guidance for animal studies to better inform compound progression decisions. [ABSTRACT FROM AUTHOR]