Clinical pharmacology of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo (7.4.1.0(2,7).0(10,12) tetradeca-2,4,6-trien-6,9-diyl diacetate (FK 973).

FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.

Depletion of patients' plasma tryptophan using tryptophan side-chain oxidase columns.

The use of the enzyme tryptophan side-chain oxidase, isolated from Pseudomonas XA, was explored in 3 patients with refractory acute lymphocytic leukemia. Patients were given either a low-tryptophan diet or tryptophan-free hyperalimentation, prior to and during therapy. Their plasma, separated by pheresis, was continuously passed through a tryptophan depletion column containing the immobilized tryptophan side-chain oxidase. Up to 4 plasma volumes were passed through the column daily, 5 days per week for 2-3 weeks, and plasma tryptophan levels, both free and total, were measured by high-performance liquid chromatography. Pre- and postcolumn plasma samples were collected throughout the pheresis procedure. All postcolumn plasma samples had unmeasurable tryptophan levels throughout the treatment period, whereas precolumn samples were always measurable. Generally, tryptophan levels of plasma isolated from peripheral blood decreased after therapy, but rebounded by the next day. The enzyme depletion column reduces circulating plasma tryptophan levels, and its use is well tolerated by patients. However, further development of this method will require study of the effects of diet and of the duration, interval, and frequency of use of this column on therapeutic efficacy. Problems include difficulties with extended diet compliance and apparently intensive mobilization of tryptophan from body stores, which may preclude the clinical application of this enzyme depletion column.

Clinical pharmacology of combined oral uracil and ftorafur.

Phase I clinical trials of the combination of oral uracil with ftorafur (Ft) were conducted in patients with solid tumors over either a 5-day (345 mg/m2/day) or a 28-day (160 mg/m2/day) period. The uracil dose, which was four times the Ft dose (molar basis), was previously shown to be optimal at inhibiting the degradation of 5-fluorouracil (5-FU). Pharmacology was performed on the first dose of the first day of therapy. Ft was measured by HPLC, whereas uracil and 5-FU were measured using GC/MS. Plasma levels were highest for Ft, followed by uracil and 5-FU at all time points. Peak and trough levels after selected subsequent doses were also measured; these varied in the individual from day to day. Maximum plasma levels (Cpmax) for Ft, uracil, and 5-FU except in one patient were achieved at 0.6-2.1 hr, 0.6-4.1 hr, and 0.7-2.0 hr, respectively. Generally, lower doses yielded more rapid decay of 5-FU and uracil levels than did higher doses. No correlation was observed between myelotoxicities (granulocytopenia and leukopenia) and the Cpmax and AUC0-6hr of Ft (p > 0.2). However, after the highest uracil and Ft dose (approximately 300 mg/m2/Ft study dose), the Cpmax and AUC0-6hr values of 5-FU revealed significant differences (p < 0.05) in three patients each with and without myelotoxicity. These associations were similarly observed with uracil. Our findings thus indicate that measuring plasma uracil and more importantly, the 5-FU levels, may predict hematological toxicity and enable subsequent dose adjustments.

Metabolism and disposition of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide Hcl (LY 195448) in rodents.

The disposition and metabolism of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide HCl, or LY 195448 (LY), were studied in rodents 1 hr following a single iv injection of 14C-LY at 30 mg/m2 (10 mg/kg mice and 5 mg/kg rats), In all tissues and carcases, recovery of 14C was nearly complete. The majority of radioactivity was recovered from intestine (40%) whereas liver and urine accounted for 10% each, kidney for 3-5%, and plasma for 1-3% of total administered radioactivity. Analyzing by HPLC and TLC, para-hydroxy-LY (para-OH-LY) in addition to unchanged drug, was found in all tissues. Meta-OH-LY was detected only in urine, intestine and kidney. These metabolites were found to be conjugated with either glucuronide or sulfate moieties. Peaks coeluting with authentic para-OH-meta-methoxy-LY and di-OH-LY were also observed.

Clinical pharmacology of trimetrexate.

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.