Brequinar sodium (DUP 785, NSC 368390) is a novel quinoline-carboxylic acid derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its novel chemical structure. This compound inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which catalyzes the conversion of dihydroorotate to orotate, leading to a blockage in the pyrimidine de novo biosynthesis. A total of 43 patients received 110 courses of Brequinar sodium by short-term intravenous (i.v.) infusion, which was repeated every 3 weeks. Dose escalation was initially based on a modified Fibonacci scheme. After pharmacokinetic data from mice and man became available, a pharmacologically guided dose escalation was used; at toxic levels, dose escalation was applied on the basis of clinical judgement. The dose-limiting toxicities were myelosuppression, mucositis, skin rash, nausea and vomiting. The maximum tolerable doses for poor- and good-risk patients were 1,500 and 2,250 mg/m2, respectively. One mixed response was observed in a patient with papillary carcinoma of the thyroid. The recommended doses for phase II studies are 1,200 and 1,800 mg/m2 Brequinar sodium, given by a 1-h i.v. infusion every 3 weeks to poor- and good-risk patients, respectively.
The pharmacokinetics of the novel antipyrimidine agent Brequinar sodium (NSC 368390; DUP 785) was studied in 23 patients with solid tumors during the phase I study of this compound. The drug was administered by short-term (10-60 min) intravenous infusion every 3 weeks. The doses ranged from 15 to 2250 mg/m2. At doses higher than 1500 mg/m2 the areas under the plasma concentration vs. time curve (AUC) increased non-proportionally, while the total body clearance (Clt) dropped substantially, indicating non-linear pharmacokinetics of the drug. Brequinar sodium showed a triphasic decay of plasma concentrations with half-life ranges of 11.1-36.6 min, 1.7-6.9 h and 12.5-25.0 h, respectively. The volume of distribution (Vdss) ranged from 4.4 to 10.6 l/m2. The total body clearance (Clt) ranged from 6.9 to 22.1 ml/min with a small contribution of the renal clearance (0.04-0.4 ml/min). Up to 7 days, the cumulative urinary excretion (CUE) and the cumulative fecal excretion (CFE) ranged from 0.4 to 8.3% and from 7.7 to 18.3% of the dose, respectively. There was evidence for the presence of drug metabolites in urine and feces. There was no drug accumulation with repeated administration of Brequinar sodium by the above mentioned drug schedule. The ratio between the plasma AUC at the maximum tolerable dose (MTD) in man and that at the mouse LD10 was 0.8, while the ratio between the respective doses was 5.7. The ratios between the AUC in patients and that at the mouse LD10 were applied to guide dose escalation in the phase I study. The results of the above mentioned pharmacokinetic studies were useful for the choice of an optimal schedule for phase II trials of Brequinar sodium.
27 patients (aged 15–55 years) with relapsed acute myelogenous (AML) and lymphoblastic leukaemia (ALL), and with lymphoblastic non Hodgkin's lymphoma (NHL) have been treated with intermediate dose cytosine arabinoside (AraC, 1 g/m2 q 12h x 12) and 3 d of m‐AMSA (20 patients), 90–115 mg/m2 daily, or daunorubicin (7 patients). 18 of them attained a complete remission (AML 10/14, ALL 3/5, NHL 5/8). 7 patients received consolidation treatment with 1–2 courses comprising 4 d of AraC (3 g/m2 q 12 h x 8) and m‐AMSA (90–115 mg/m2) on d 5 of each course. 2 patients underwent allogeneic bone marrow transplantation and 9 received no further treatment after remission induction.
In addition to vomiting, fever and conjunctivitis, toxicity in 6 patients included a combination of severe diarrhoea, fever and signs of paralytic ileus. 3 of them died during the pancytopenic phase. The pancytopenic period ranged from 16–25 d (median 21 d) after the remission induction and 14–21 d (median 19 d) after the consolidation course. Median remission duration was 5 months for those patients who received no treatment after remission induction and >9 months (4+‐16+ months) for the patients who received consolidation courses. Increased dosages of AraC are active in relapsed leukaemia and lymphoma, although optimal dose and schedule are still undetermined.
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