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R Grunewald

Publications and source records attributed to R Grunewald.

6 recordsLinked to original sources
PubMed1992

Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study.

PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS: The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS: The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION: Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.

Adolescent↗
PubMed1991

Saturation of 2',2'-difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine.

The plasma and cellular pharmacology of 2',2'-difluorodeoxycytidine (dFdC, Gemcitabine) was studied during a phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m2 per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5'-triphosphate (dFdCTP), were determined in mononuclear cells of 22 patients by anion-exchange high-pressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m2 per 30 min, during which steady-state dFdC levels of 15-20 microM were achieved in plasma. A comparison of patients infused with 800 mg/m2 over 60 min with those receiving the same dose over 30 min demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10-15 microM dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable. In the design of future protocols, a dose rate should be considered that produces maximal nucleotide analogue formation, with increased intensity being achieved by prolonging the duration of infusion.

Antimetabolites, Antineoplastic↗
PubMed1991

A phase I clinical, plasma, and cellular pharmacology study of gemcitabine.

A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.

Adult↗
PubMed1990

Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (Gemcitabine) administration in leukemia.

The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 microM during infusion of 800 mg/m2/h, 9.4 microM during infusion of 400 mg/m2/h, and 5.6 microM at 267 mg/m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 2.3- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5-100 microM dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15-20 microM dFdC. We conclude that a dose rate of greater than 400 mg/m2/h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.

Adult↗
PubMedDate not supplied

Prolymphocytic leukemia with suppressor T-cell phenotype: report of two cases.

The clinical course of two patients with prolymphocytic leukemia of the suppressor T-cell phenotype is presented. Diagnosis was established by specific monoclonal antibody tests, cytochemical, ultrastructural and cytogenetic studies. The bone marrow showed a diffuse infiltration with medium sized lymphocytes displaying a prominent nucleolus. Both patients presented with pronounced splenomegaly, diffuse lymphnode involvement, leukocytosis, thrombocytopenia and anemia. One of them was refractory to chemotherapy using CHOP, Asparaginase, IMVP16, and irradiation to the spleen. He benefited from prednimustin and repeated leukaphereses, without reaching complete remission (C.R.). The second patient achieved a C.R. of 4 months duration with CHOP-Bleomycin. Survival was 16 and 11 months respectively.

Female↗