Pharmacokinetics of the novel antiestrogenic agent toremifene in subjects with altered liver and kidney function.

OBJECTIVES: The pharmacokinetics of toremifene was investigated in an open study with four parallel groups of 10 subjects each. Subjects with impaired liver function (biopsy-proven liver disease), activated liver function (drug-induced), and impaired kidney function were compared with normal subjects. METHODS: A single oral 120 mg dose of toremifene was administered after an overnight fast, and blood samples were collected over 28 days. Serum levels of toremifene and its metabolites were determined; appropriate pharmacokinetic parameters were calculated and statistically evaluated. RESULTS: In normal subjects, the average peak level of 414 ng/ml toremifene was achieved at 3 hours after dosing, the terminal half-life was 6.2 days, apparent oral clearance was 5.1 L/hr, apparent volume of distribution was 958 L, and the fraction not bound to protein was 0.3%. The peak level (130 ng/ml) of the major metabolite, N-demethyltoremifene, appeared in serum with large variation in the time to peak level (median, 3 days) and a terminal half-life of 21.0 days. Low levels of deaminohydroxytoremifene were also measured, and two other metabolites could be quantified at some time points in some patients. The elimination rate of toremifene and the main metabolite was significantly increased in patients with activated liver function, resulting in decreased terminal half-lives (3.0 days and 4.5 days, respectively), and was decreased in patients with impaired liver function (10.9 days and 29.6 days, respectively). The subjects with impaired kidney function showed normal elimination kinetics. CONCLUSION: Liver, but not kidney, function should be taken into account when toremifene is administered.

Effect of the Choice of Primary Chemotherapy on the Cumulative Length of Stay in Hospital for Multiple Myeloma.

The actual use of hospital beds for patients with multiple myeloma was calculated from a randomised trial of primary treatment with either melphalan and prednisone (MP, 66 patients) or intensive combination chemotherapy with vincristine, cyclophosphamide, lomustine, melphalan and methylprednisolone (MOCCA, 64 patients). The survival of the patients was similar in both arms, and the samples, 20 and 32 patients, respectively, were well representative for the whole arms. The average numbers of hospital days were similar fur both arms. For the first year MP 33.2 (SD 27.6) vs. MOCCA 32.1 (SD 19.0), and during the first to 4th years 78.5 (SD 45.9) vs. 67.8 (SD 34.1). For the year of death it was 50.4 (SD 33.1) vii. 36.3 (SD 27.0), respectivelly. Thus the choice of primary chemotherapy whether conventional or more aggressive had no influence on the actual number of in-patient hospital days concerned. When the combination chemotherapy schedule is well tolerated it can be administered just as well on an ambulatory basis or by using it with very short admissions. It seems that the need for inpatient care for patients with multiple myeloma is mostly related to the complications of the disease itself and to intercurrent disorders including infections.