Programs for biosimilar drugs usually need at least one preclinical study to support the clinical phase of development. This study must have pharmacokinetic, immunogenicity and toxicological components and provide insight into the similarities and differences (i.e., comparability) between the biosimilar and the innovator drug.

This white paper focuses on one component of such a study: Demonstrating the comparability of the toxicokinetics of the biosimilar versus the innovator drug.

The term “comparability” comes from the biosimilar guidelines which can be found on the European Medicines Agency (EMA) web site1. These state that at least one non-clinical repeat dose toxicology study with toxicokinetic, immunogenicity and pharmacodynamic endpoints should be considered for a biosimilar drug.

However, the distinguishing feature of the pivotal toxicology study for a biosimilar drug is that the sponsor must demonstrate that the biosimilar and the innovator drug are “comparable” with respect to both toxicity and toxicokinetics.

The former means that the biosimilar and the innovator drug exhibit comparable toxicology profiles. The latter means that it is necessary to determine if the biosimilar and the innovator drug have comparable or similar

How is toxicokinetic comparability determined?

Where feasible, we have taken the conservative approach and designed preclinical toxicokinetic studies that compare the relative systemic exposure of the biosimilar and the innovator using pharmacokinetic and statistical approaches typically reserved for human equivalence trials.

Designing these studies in animal models requires an adaptation of the approach used for humans. Specifically, for some species, the number of blood samples needed to robustly evaluate the pharmacokinetic characteristics of a drug is a rate- limiting factor in the evaluation.

In some EU member states, the extravasation volume and the frequency of exsanguination is limited. For biosimliar compounds, particularly those with long half-lives, this limits the ability to fully characterize and compare the elimination phase.

These are complex molecules and slight differences in the biochemical structure may result in differences in systemic clearances between the biosimilar and the innovator compound. In general, the more robust the evaluation, the greater the confidence is in the comparability of the two products. In most cases we recommend conducting pilot studies in the animal model. From this data we get our first look at the pharmacokinetics of the biosimilar drug using the clinical route of administration compared to the innovator drug. Lessons learned from these pilot studies help us plan the pivotal study. For example, from the variability in the pilot studies we estimate the number of animals needed, the number of blood samples and the optimal placement of these samples (i.e. time points) for the pivotal animal study. In toxicology studies using a species having a small blood volume, the blood sampling times are staggered. Exposure at any one sampling point is based on a different subset of animals relative to the adjacent sampling points and animals are sacrificed at the time of exsanguination.