Page 327 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

data). On the other hand, a 35% dose reduction for carriers of c.2846A>T is not proven to be more adequate compared to a 50% dose reduction. In addition, a 50% dose reduction would be more feasible in clinical practice. The c.1236G>A variant has a large variation in DPD enzyme activity with a median of 74% activity of DPYD wild-type patients in our study. However, our study showed that a 25% dose reduction in carriers of c.1236G>A did not result in a reduction of the relative risk for these patients, as some patients require a larger dose reduction.15 As was commented by Amstutz and Largiader, our study would support a 50% dose reduction in carriers of both c.2846A>T and c.1236G>A, provided that this should be used as a starting dose.46 Further dose adaptations guided by the onset of toxicity (dose titration) are possible and should be applied slowly, as fluoropyrimidine-induced toxicity can occur with a certain delay.
Currently, there are no specific recommendations available on how to apply these additional dose adaptations. Recently, Kleinjan et al. retrospectively investigated dose escalations in DPYD variant allele carriers according to a local pre-specified protocol.47 Eleven DPYD variant allele carriers were identified, of which six patients (55%) received a dose escalation of 15%. In two patients, the dose had to be reduced again due to toxicity, resulting in a median dose escalation of 9%. In two DPYD variant allele carriers (18%) the initially lower dose was further reduced. In the clinical trial (chapter 5) no pre-specified protocol was available for dose adjustments. We identified 85 DPYD variant allele carriers. In eleven patients (13%) the dose was increased by 21% on average, yet in five patients the dose had to be reduced again and one patient had to stop treatment, resulting in a mean dose escalation of 13%. In ten patients (12%) initially lower dosages were further reduced by 20% on average. Without a pre-defined protocol, the dose was increased in fewer patients, yet the dose adjustment steps were larger. The dose reductions applied after a dose escalation point out the importance of slowly applying dose escalations in relatively small steps. The additional dose reductions required after the low initial dose, again point out the variation in DPD enzyme activity in DPYD variant allele carriers, and could explain the higher overall severe toxicity rates in DPYD variant allele carriers of the clinical trial (39% versus 23% for wild-type patients).15
Dose adjustments after exposure to 5-FU or capecitabine
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General discussion
Therapeutic drug monitoring (TDM) is a useful method to guide dose adaptations after start of therapy. Unfortunately, the use of TDM for fluoropyrimidines in the Netherlands is limited as the wide majority of patients (approximately 90%) are prescribed capecitabine over 5-FU. For TDM of 5-FU defined target ranges and dosing algorithms are available.48-50 Yet, the intracellular conversion of capecitabine into 5-FU and its metabolites result in low plasma concentrations of capecitabine and its metabolites, which makes it more difficult to develop TDM protocols for capecitabine.51 Until such protocols have been established, TDM of fluoropyrimidines in the Netherlands will be used sparingly. Furthermore, TDM can be used to monitor drug levels after start of treatment, not to determine initial dose reductions in order to prevent quick-onset severe fluoropyrimidine-induced toxicity.
A method to determine if initial dose adaptations in patients are required, is to expose the patient prior to treatment to a 5-FU test dose of 250 mg/m2.52,53 After the test dose, 5-FU
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