PHASE-I TRIAL AND PHARMACOKINETICS OF ACIVICIN ADMINISTERED BY 72-HOUR INFUSION

  • 1 January 1983
    • journal article
    • research article
    • Vol. 67  (7-8) , 683-692
Abstract
Acivicin, an L-glutamine antagonist, was administered to 37 evaluable patients with refractory advanced solid tumors in a phase I trial. Evaluable 72-h i.v. infusions (67) were given at 3- to 4-wk intervals. Doses ranged from 3.0-90 mg/m2 per course. Reversible CNS toxicity was dose-limiting and included lethargy, somnolence, anxiety, hallucinations and paranoid psychoses. Of 5 patients, 4 experienced unacceptable CNS toxicity at 90 mg/m2. Of 8 patients, 3 experienced reversible diaphoresis and chills without fever at 75 mg/m2, and 2 had dizziness and ataxia. Hematopoietic toxicity, nausea, emesis and diarrhea were mild and dose-related. One patient developed a blue-green discoloration of the infusion arm. Serial plasma and urine specimens from 13 patients were assayed for acivicin using a microbiologic method. Peak plasma levels at the end of the 72-h infusions correlated with dose and ranged from 0.09-1.10 .mu.g/ml. When data from 6 patients were fitted to a 2-compartment open model, .alpha.-half-life ranged from 1.1-63 min; .beta.-half-life ranged from 338-629 min. Renal clearance ranged from 6-24 ml/min, and nonrenal clearance accounted for 58-83% of the total drug clearance. CNS toxicity correlated with plasma acivicin levels which exceeded 0.9 .mu.g/ml for > 16 h, but not with peak plasma levels or with the integrals of the concentration .times. time curves. Minor responses were seen in 1 patient with melanoma, in 1 with epidermoid pulmonary carcinoma and in 2 with colon carcinoma. A starting dose of 60 mg/m2 per course was recommended for phase II trials, with possible escalation to 75 mg/m2 in the 2nd course if the drug was well-tolerated.