The influence of morning versus evening administration on tamoxifen pharmacokinetics.

Tamoxifen is still an important and effective drug for the treatment of breast cancer. However, tamoxifen has to be converted to the (most abundant) active metabolite endoxifen. CYP-mediated metabolism plays an important role in the
metabolism of tamoxifen into endoxifen. CYP-enzyme activity, biliary excretion and expression of transporters are suggested to be influenced by a circadian rhythm. This suggests that tamoxifen pharmacokinetics may be influenced by circadian rhythm and time of tamoxifen administration may influence endoxifen concentrations.

In this study we will investigate the influence of morning versus evening administration on the pharmacokinetics of tamoxifen.

Patients who are treated with tamoxifen will be included in this trial; nine patients who use tamoxifen in the morning and nine patients who use tamoxifen in the evening. Patients will switch from administration in the morning to administration of tamoxifen in the evening (or vice versa). During both periods, patients will undergo a 24-hour pharmacokinetic sampling period. Blood samples will be analysed by a validated LC-MS/MS method. The differences in pharmacokinetic parameters will be statistically evaluated using a paired Student's t-test or Wilcoxon rank sum test in case of a non-gaussian population.

Amendment: To observe whether tamoxifen pharmacokinetics differ between morning (8 a.m.), afternoon (1 p.m.) and evening (8 p.m.) dosing, possibly reaching higher levels of tamoxifen and active metabolites after dosing at 1 p.m., a third time-point (1 p.m.) of tamoxifen administration will be included in the study (to investigate the effects on pharmacokinetics).

Tamoxifen pharmacokinetics may be influenced by circadian rhythm. Endoxifen exposure may differ between morning administration of tamoxifen and administration in the evening.

Amendment (1-apr-2013): Tamoxifen pharmacokinetics may be influenced by circadian rhythm. Endoxifen exposure may differ between morning administration of tamoxifen and administration in the afternoon and evening.

1. Prior to the study: Informed consent;

2. Tamoxifen administration in the morning/evening* for at least 4 weeks;

3. Pharmacokinetic sampling during a 24-hour (clinical) period;

4. Patients will switch to administration of tamoxifen in the morning/evening*;

5. Tamoxifen administration in the morning/evening* for at least 4 weeks;

6. Pharmacokinetic sampling during a 24-hour (clinical) period;

7. Evaluation of adverse effects during the study.



* = dependent on group.



Pharmacokinetic parameters (AUC, Cmax, Tmax) will be evaluated and
compared between morning and evening administration.

Amendment:

1. Patients will switch to administration of tamoxifen in the afternoon;

2. Tamoxifen administration in the afternoon (~ 1.00 PM) for at least 4 weeks;

3. Pharmacokinetic sampling during a 24-hour (clinical) period.

Patients will switch from administration of tamoxifen in the morning to administration in the evening or vice versa.
Amendment: Patients will switch for a second time from tamoxifen administration in the morning/evening to administration in the afternoon.