Page 163 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Safety analysis on DPYD genotype-guided dosing
number of patients with a DPYD variant of whom we also obtained pharmacokinetic data (Supplementary Table 3) firm conclusions on the basis of pharmacokinetic measurements alone cannot be drawn.
The mean DPD enzyme activity for c.1236G>A was approximately 20% reduced, but a large variation in DPD activity was found (Figure 3), which suggests that a proportion of patients needs a larger dose reduction, while other patients might even tolerate a full dose. This is also in line with the large variation in pharmacokinetic exposure seen in c.1236G>A carriers. Individual dose titration is important to ensure an adequate and safe dose for all patients. Therefore, we recommend a more cautious initial dose reduction of 50%, followed by close monitoring and individual dose titration.
The mean value for c.2846A>T DPD enzyme activity was approximately 35% reduced compared to normal. These DPD activity measurements show that 25% dose reduction might not be sufficient for most of the patients, and this could be an explanation for the higher toxicity risk in this patient group. A more cautious initial dose reduction of 50% should be considered in these patients as well.
In this study, initially reduced doses were escalated in eleven out of 85 (13%) DPYD variant allele carriers, although only five patients were able to tolerate this escalated dose. In DPYD wild-type patients dose escalations are uncommon in clinical practice (3% in our study, mostly patients who started with an initially reduced dose as a precaution measure).
Our study was performed in a daily clinical care setting in general regional hospitals and a few academic centers, demonstrating the feasibility of implementation of upfront DPYD screening. In order to make DPYD-guided dosing feasible in all hospitals, it is important that the turn-around time for DPYD genotyping is short to prevent a delay in the start of treatment. Participating laboratories in our study had a turn-around time of a few days to a maximum of a week.
A limitation of this study is that a historical cohort of DPYD variant allele carriers treated with full dose was used as control, and no direct comparison was made with a control cohort within the study. Inherently to this chosen design, differences between the study populations could have influenced the observed toxicity outcomes. However, this study design was chosen as a randomized clinical trial is considered unethical in this context, since it is known that DPYD variant allele carriers are at increased risk of severe toxicity when treated with a full dose of fluoropyrimidines.25 A previously performed clinical study was stopped prematurely as a patient in the arm without dose individualization died due to treatment-related toxicity.26
This study focused on toxicity and did not evaluate survival or other effectiveness outcomes, as this was considered not feasible due to the large variation in tumor types and treatment regimens. We did, however, perform pharmacokinetic measurements, which suggest that applied dose reductions in DPYD variant allele carriers did not result in under- dosing.
The four DPYD variants investigated in this study are especially relevant to Caucasian populations. For ethnicities other than Caucasians, more research on the frequency and clinical relevance of these and other DPYD variants is recommended.27 In our current study, homozygous and compound heterozygous DPYD variant allele carriers were not included and
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