Model informed precision dosing
If the criteria for TDM are met, the application in the clinical setting
can be improved by the use of population PK/PD models to facilitate
model informed precision dosing (MIPD). Such models have been developed,
validated and applied in research for decades -for small molecule drugs
and increasingly also for biologicals. However, the implementation of
such tools into the clinical use of biologicals has been limited, which
may also reflect the sparse evidence for the role of TDM in this
setting. There are examples especially in the therapy of inflammatory
bowel disease and some other immune diseases where MIPD has been
explored to guide personalization [20-23]. Also for a drug like
alemtuzumab a PK/PD model was developed for patients treated for chronic
lymphocytic leukaemia (CLL) [24]. Although the model performed well
in this setting, the study highlighted the nonlinear and time-dependent
pharmacokinetics due to changes in WBC count for the CLL patients, which
again illustrates that models may not be applied in other patient
populations like transplanted patients. A lot of work has been invested
to better understand the contributions of physiological processes and
drug characteristics that govern the PK and PD and hence can guide the
model development. The more complex descriptions may be more relevant in
the process of mAbs development [19, 25], however there may also be
lessons to learn for models. How the application of a PK/PD model can
improve the personalization of a biologic like eculizumab, has been
elegantly demonstrated by the work of a group at Cincinnati Children’s
Hospital. The treatment of transplant-associated thrombotic
microangiopathy (TA-TMA) in children and young adults undergoing
hematopoietic stem cell transplantation (HSCT) was prospectively
individualized by support of a model that was proven effective for
eculizumab versus outcome of these severe adverse effects of the HSCT
[26, 27].