Pharmacokinetics of Brequinar sodium (NSC 368390) in patients with solid tumors during a phase I study

Abstract

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.

Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia

“…BAY-155 was synthesized according to the methods outlined in patent application WO2017207387A1. Inhibitor concentrations for EPZ-5676, Brequinar, and OTX015 used in this in vitro study are lower as plasma concentrations measured in clinical studies [24, 26, 29]. Plasma concentrations of BAY 1251152 in humans are not yet reported.…”

Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression

“…In that study ( 26 ), inhibition of DHODH by BRQ induced the differentiation of immortalized GMPs into mature myeloid populations, namely neutrophils. In fact, years ago, BRQ was tested as an antineoplastic agent against multiple solid tumor types, and although the treatment was generally well tolerated, clinical efficacy was not observed across the various clinical trials ( 29 – 31 ). While BRQ treatment as a direct anticancer agent was not effective, we reasoned that BRQ may be effective in combinations, acting as an anti-MDSC therapeutic that could boost immunotherapy efficacy.…”

The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia

“…The DHODH inhibitor brequinar (NSC 368,390, DuP-785) demonstrated potent in vitro and in vivo anti-tumor activity across multiple tumor models [3]. Brequinar was quickly advanced to phase I clinical trials in patients with advanced solid tumor malignancies [4–6]. While brequinar was generally well-tolerated, and demonstrated occasional durable responses, the clinical experience was disappointing across more than a dozen trials encompassing more than 500 patients [7–11].…”