Pharmacological study of chronomodulated capecitabine therapy

Capecitabine is a widely used oral prodrug of 5-fluorouracil (5-FU). Enzymatical conversion of capecitabine subsequently by carboxyl esterase (CES), cytidine deaminase (CDA) and thymidine phophorylase (TP) is warranted for the formation of 5-FU. However, the clinical application of capecitabine is limited by treatment failure and poorly predictable severe toxicity (especially diarrhea and palmar-plantar erythrodysesthesia (PPE)). Treatment safety and efficacy may be improved by synchronization of capecitabine therapy to the circadian rhythm of the 5-FU degrading enzyme dihydropyrimidine dehydrogenase (DPD) and its drug target thymidylate synthase (TS). Approximately 80% of 5-FU is metabolized by DPD. Earlier studies, including an observational study performed by our research group, showed that DPD activity fluctuates over the twenty-four hours of the day. This so called circadian rhythm of DPD is characterized by low metabolic capacity during day-time and peak metabolic capacity during the night. Nocturnal DPD activity is approximately 60% higher compared to DPD activity in the afternoon.
Consequently, metabolism of 5-FU is most likely increased during the night because of high DPD activity. Besides circadian activity of DPD the enzyme thymidylate synthase (TS) also shows circadian activity. The enzyme TS displays trough activity during the night. Exposure to 5-FU when TS activity is low has been associated with improved 5-FU tolerability. Circadian rhythms of DPD and TS presumably affect capecitabine treatment pharmacokinetics, safety and tolerability. Safety and the maximum tolerated dose (MTD) for Xeloda® have been determined in earlier phase I trials for continuous and intermittent (day 1-14 of a 21-day course) BID treatment schedules with Xeloda®. Major limitations of these studies were that circadian rhythms in 5-FU metabolism were not taken into account. Chronomodulated capecitabine therapy, indicating that capecitabine therapy is synchronized to circadian rhythms of DPD and TS, might be advantageous for Xeloda® BID treatment. Therefore, we aim to determine the feasibility of chronomodulated capecitabine in a pharmacological phase I clinical study. A new capecitabine dosing schedule is developed by population modeling of capecitabine pharmacokinetics and DPD activity. Capecitabine will be administered continuously on day 1-21 (arm A) and intermittently on day 1-14 (arm B) of 21-day BID dosing schedules. For both study arms, the morning dose will be administered at 9:00 hours (h) and the late evening dose at 24:00 h. Chronomodulation will be obtained by using a relatively high evening dose of capecitabine.



Country of recruitment: The Netherlands

Circadian rhythms of dihydropyrimidine dehydrogenase and thymidylate synthase might affect capecitabine tolerability. It is expected that high dose capecitabine during the night is better tolerated because of these circadian rhythms.

Screening: PD sampling for DPD, TS and TP activity;

Day 7 and 8: PK sampling capecitabine (metabolites), PD sampling for DPD, TS and TP activity;

End of treatment: PD sampling for DPD, TS and TP activity.



Safety measurements will be performed every week of the first treatment course, and every first day of subsequent treatment courses.

Capecitabine will be administered exactly at 9:00 h and 24:00 h on day 1-21 (arm A) and 1-14 (arm B) of a 21-day treatment schedule. To obtain chronomodulation the ratio of the morning to the evening dose will be maintained at 3(morning dose):5(evening dose).