Dose range finding approach for rodent preweaning juvenile animal studies

Abstract

Objectives Strategies for conducting juvenile dose ranging studies before definitive toxicity juvenile animal studies (JAS) have evolved, but the aim of demonstrating study design robustness and efficient animal use remains the same. The objective of dose selection is to identify a strategy to achieve consistent systemic exposure for the duration of the JAS while maintaining exposure separation between dose groups. For preweaning rodents this can prove challenging, as these studies typically treat animals over a broad period of considerable organ development. Materials and Methods In our experience, over 45 rodent juvenile studies (dose range, definitive or investigative) were conducted over 20 years to support pediatric medicine development. In most cases (86%, 12/14), preweaning rodents required decreased doses of test articles than adult rodents; the majority (83%, 10/12) were due to increased systemic exposures in immature animals at the same doses. Thus, extrapolating tolerability and exposure data from adults is not ideal and should not take the place of well‐designed juvenile dose range studies. Results/Discussion/Conclusion We propose a phased dose‐range‐finding approach by first conducting a tolerability phase with a few animals at a starting age corresponding to the youngest clinical starting age, spanning a wide range of doses, then a dose range phase with larger group sizes and fewer doses; both phases incorporate toxicokinetics. Often, exposure was higher in preweaning animals and decreased as animals matured postweaning (postnatal day, PND 21 and older), supporting an age‐based dose adjustment strategy. Case studies demonstrate dose adjustment approaches incorporating dose increases or decreases or changes in dose frequency.

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“…(ii) Toxicity-and-toxicokinetics phase (round 2 and round 3). Following large decreases in systemic exposure evident in the tolerability phase (between PND 13 and PND 21 at 100 and 1,000 mg/kg/day), a dose escalation approach was used in an attempt to maintain consistent systemic exposures in all dose groups throughout the treatment period ( 46 ).…”