Multiple-dose pharmacokinetics of epirubicin at four different dose levels: studies in patients with metastatic breast cancer

Summary Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m². In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant _1/2, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant _1/2, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant _1/2, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c ₂+62.5×c ₂₄+157.7 (r=0.953).This work was supported by the Lundbeck Foundation, the Michaelsen Foundation and Farmitalia Carlo Erba Ltd.     

Validity of a questionnaire survey: the role of non-response and incorrect answers

Errors in questionnaire surveys are usually of one of two sources: non-responses or incorrect answers. The aim was to investigate the validity of a questionnaire survey and to estimate the respective bias of these answers. Of 9,283 subjects selected to receive a questionnaire by post, 3,949 (43%) responded, and, of these, 3,400 correctly reported their Swedish social security number. Answers in the questionnaire survey were given as proportions of the claims registered at local insurance offices. In the group of respondents who had correctly reported their social security number, the answers were compared individually with the registrations in dental insurance claims. In Sweden, these claims are labeled with the patient's social security number and it is thereby possible to make such comparisons. It was shown that errors were caused by non-response and also by respondents giving incorrect answers. Incorrect answers accounted for approximately one-third of the total bias. The remaining bias was caused by a non-response error. It is concluded that questionnaire studies have a bias caused by both non-response and incorrect answers and that together these can be substantial. Scientific reports that include questionnaire surveys must describe the procedure carefully. If possible, other sources of information should be considered.