Evaluating the Feasibility of
TDM
Once drug exposure-response studies successfully define a target
therapeutic concentration range or efficacy cutoff, prospective
dose-adjustment trials intended to demonstrate that TDM can be
implemented should be initiated (Figure 1, Stage 3). The primary outcome
of this type of study is the proportion of patients starting the
treatment under- or over-exposed who successfully achieve therapeutic
blood drug levels following recommendations for dose
adjustments.1–5,32–35 Such TDM feasibility studies
may compare the prevalence of therapeutic exposure before and after dose
adjustment recommendation in the same group of subjects or, preferably,
with a separate control arm.
The data on feasibility of dose individualization generated by such
studies is crucial, as it can identify a number of reasons why a dose
adjustment recommendation is not actually carried out. A substantial
number of physicians will not follow the dosing
advice.24 For example, doctors may be hesitant to
increase the dose beyond the highest FDA-approved dose or the maximum
tolerated dose established in clinical trials. On the other hand, most
oncologists would be rightfully reluctant to reduce the dose in the
absence of observable toxicity. Lack of reimbursement for increased
doses of these often very expensive drugs may also stifle dose
optimization. Finally, medication compliance issues may further reduce
feasibility of optimizing drug exposure through dose individualization.
As mentioned above, numerous examples of such studies evaluating
feasibility of TDM for oral small molecule anticancer drugs are
available and many of them indeed succeed in increasing the proportion
of patients with drug levels in the therapeutic
range.1–5,32–35 An example that deserves special
mention is the recently described study of the Dutch Pharmacology
Oncology Group (DPOG).33 The primary objective of this
ongoing prospective multi-center trial involving 600 patients is to
halve the proportion of patients with a drug exposure below the TDM
target after 2 potential PK-guided interventions which, for most of the
23 oral anticancer drugs that are being monitored, will be after 12
weeks of treatment. The secondary objectives are to examine tolerability
and outcome parameters such as objective response rate, time to
progression, progression free survival, etc.