RESUMO
An uncontrolled open prospective dose escalation study of daily constant-rate 24-h i.v. pentoxifylline (PTX) infusions was performed in 24 consecutive adult patients with hematologic malignancies undergoing allogeneic BMT. The objective of this study was to determine the maximum tolerable dose and to evaluate steady-state plasma concentrations of PTX and its major active 5-hydroxylated metabolite (MI) with this application route. On each of three dose levels of PTX (10, 15 and 20 mg/kg/day), eight patients were enrolled in this study. The prominent dose-dependent and dose-limiting adverse effect attributable to PTX infusions was moderate to severe nausea and vomiting which occurred on the 15 mg/kg and 20 mg/kg dose levels. In addition, one patient on each of the higher doses developed central nervous system toxicity which manifested as acute obtundation and myoclonias. Monitoring of steady-state plasma concentrations revealed that metabolite MI contributed 70-80% to both active compounds with a dose-dependent increase of parent drug and metabolite MI concentrations. In patients pretreated by high-dose busulfan and cyclophosphamide (CY), steady-state plasma concentrations of metabolite MI were significantly increased on all dose levels over those of patients who received total body irradiation and CY as a preparative regimen. Furthermore, impairment of excretory liver function led to significant accumulation of parent drug and metabolite MI. In conclusion, constant i.v. PTX infusions in allogeneic marrow transplant recipients are limited by dose-dependent nausea and vomiting with an estimated maximum tolerable dose in the range of 10 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)
