22 VOI. I0 - I988 Pharmaceutisch Weekblad Scientific Edition short communications The bioavailability of Tamoplex| (tamoxifen) Part 3. A steady-state study in breast cancer patients P.H.TH.J. SLEE,* D. DE VOS,** D. CHAPMANw AND D. STEVENSONw Introduction In a previous paper the bioequivalence of Tamo- plex | xo mg and Nolvadex | io mg tablets was demonstrated in a single dose absorption cross-over study with a wash-out period of at least 14o days in healthy male volunteers. 1 Such a cross-over study cannot be carried out in breast cancer patients, because tamoxifen therapy cannot be interrupted for such a long period. If a short wash-out period were allowed, pharmacokinetic and pharmacodynamic interaction between the two preparations under investigation would be expected, t Therefore a steady-state study has been carried out in breast cancer patients. Methods STUDY DESIGN The plasma elimination half-life of tamoxifeta in patients at steady-statehas been reported as one week. z So at least three weeks of therapy using one preparation was thought necessary. In the study design therefore four weeks were chosen. The cross-over design of two periods of four Weeks was preceded by a cross-over design of two periods of two weeks. This was done because of the high intrapatient variability in time, anticipated on the basis of literature dataJ "S Another reason was better patient accrual and protocol compliance in a short study than in a long lasting investigation. Twelve patients were randomly allocated to treatment with either three tablets of Tamoplex| Io mg or three tablets of Nolvadex| Io mg daily. After two weeks the patients were switched to the other preparation and after two weeks a second change-over took place. After four weeks a third and final switch was made. The tamoxifen tablets were administered daily with 15o ml of water at i2.oo h. A pre-study blood sample of 5 ml was taken. Subsequent blood samples of 5 ml were drawn after I, 2, 3, 4, 5, 6, 7, 8 and i2 weeks. The blood samples were drawn at i2.oo h just prior to the daily tamoxifen dose. In this way trough values of the steady- state levels were obtained. After clotting the samples were centrifuged and the serum was collected. The serum was divided into equal samples and labelled with random numbers. The samples were stored at -2o~ until analy- sis. PATIENTS Literature data, confirmed by our pilot study, showed that patients on bidaily tamoxifen therapy reached a steady-state situation in three weeks. 3This was taken into account in the patient inclusions. Patient inclusions were: - metastatic breast cancer patients on tamoxifen therapy for at least three months; tamoxifen therapy was started with a loading dose of I6o mg (based on volunteer pharmacokinetics) and continued with a single daily dose of 30 mg at 12.oo h. The steady-state was confirmed by a pre-study sample; - patients who had given their informed consent to the study; Key words Bioavailability Breast neoplasms Drug evaluation Tamoxifen * Department of Clinical Oncolg~gy, Sint Jozef Ziekenhuis, Graaf Florisweg 77, 2805 AH Gouda, the Netherlands. ** Medical Department, Pharmachemie BV, P.O. Box 552, 2003 RN Haarlem, the Netherlands (correspondence and reprints). w Robens Institute, University of Surrey, Guildford, United Kingdom. S/ee PHTId, De Vos D, Chapman D, Stevenson D. The bioavailability of Tamoplex| (tamoxifen). Part 3. A steady-state study in breast cancer patients. Pharm Weekbl [Soil I988;Io:22-5. Abstract The bioavailability of two tamoxifen preparations (Tamoplex| and Nolvadex| was compared in a multiple dose two-way cross-over design in twelve breast cancer patients. The formulations were found to be bioequivalent. Mean steady-state serum levels of tamoxifen and N-desmethyltamoxifen were I33 ng/ml and 242 ng/ml, respectively, at a single daily dose of three tablets of Tamoplex| io mg and i28 ng/ml and 248 ng/ml, respectively, at a single daily dose of three tablets of Nolvadex | 1o rag. While there was a large interpatient as well as intrapatient variability in steady-state levels of tamoxifen and N-desmethyltamoxifen, their ratio appeared to be constant in the individual patient.