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.