Conclusion
The use of biologicals like recombinant therapeutic proteins, monoclonal
antibodies, fusion proteins and conjugates is expanding. Many of these
can be extended to off-label indications within the field of solid organ
transplantation based on available experience from their use on other,
labelled indications. However, pharmacokinetic characteristics of these
large, partly also immunogenic molecules differ from those of
traditional small molecules, and the variability may depend on factors
like target mediated elimination which complicates extrapolation from
one disease to another. So far the studies that have explored
individualization by concentration measurements and modelling have been
proof-of-concept or feasibility studies that lack the power to provide
evidence for eventual improvement in clinical outcome.
For some drugs like alemtuzumab, eculizumab, rituximab, tocilizumab and
belatacept the inter-individual variability in pharmacokinetics has been
demonstrated. The option for subcutaneous administration may reinforce
the need and the potential for individualization by TDM. A few of the
drugs mentioned -probably also for some in the pipeline- there is an
economic aspect of appropriate dosing that needs to be pursued.
Available assays and models to refine interpretation are in place, the
obstacles are in the challenges to perform trials of adequate size to
document the usefulness of TDM and model informed precision dosing.