RESUMO
Phase I and pharmacokinetic studies were performed in order to evaluate the maximum tolerated dose and the efficiency of 120 h continuous venous infusion (CVI) of mitoxantrone. 25 patients suffering from either metastatic solid tumour or refractory lymphoproliferative disease were included in the study. The starting dose was 2 mg/m2 per day and was increased by a 0.2 mg/m2 per day step dose. The main toxicity observed was leukopenia which became limiting in more than 50% of the patients receiving 2.4 mg/m2 per day (12 mg/m2 over a 120 h period); this dose was defined as the maximal tolerated dose in these pretreated patients. One partial response and three stable diseases were observed. A plasma plateau concentration of mitoxantrone (2.13 [S.D. 0.54] micrograms/1 at 2 mg/m2 per day, 2.56 [1.32] micrograms/1 at 2.2 per day and 3.46 [1.32] micrograms/l at 2.4 mg/m2 per day) was reached within 24-48 h. It was linearly related to the administered dose. The mean plasma clearance of mitoxantrone was 27.8 [14.2] l/h/m2 and the volume of distribution of the beta phase averaged 2327 [2125] l/m2. An inverse relationship was established between the mitoxantrone clearance and the degree of hematologic toxicity. This 120 h CVI mitoxantrone schedule was safe and could be repeated every 3 weeks in an outpatient setting. The relationship between mitoxantrone clearance and the drug related haematotoxicity could be used for an individual dose adjustment.
Assuntos
Mitoxantrona/toxicidade , Neoplasias/sangue , Adolescente , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/sangue , Neoplasias/tratamento farmacológicoRESUMO
A first-derivative spectroscopic method for the simultaneous determination of bound and unbound drug in human serum and serum albumin solution was developed. As an example, the binding characteristics of rifampicin were studied. In serum albumin solution, the rifampicin bound and unbound fractions were determined at 473.5 and 475.8 nm, respectively. For human serum, the unbound fraction was determined at 479.4 nm. The results obtained by the first-derivative spectroscopic method were in agreement with those obtained by equilibrium dialysis. The proposed method is very simple and accurate when applied to measurements of drug:protein binding. Moreover, it allows a direct measurement of the bound and unbound forms without any physical separation.