Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics.
Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.
Grochow
L B
LB
Johns Hopkins Oncology Center, Baltimore, MD 21205.
Noe
D A
DA
Dole
G B
GB
Rowinsky
E K
EK
Ettinger
D S
DS
Graham
M L
ML
McGuire
W P
WP
Donehower
R C
RC
D000328:Adult; D000368:Aged; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D004334:Drug Administration Schedule; D004338:Drug Combinations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004341:Drug Evaluation; D005260:Female; D005965:Glucuronates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects; D013045:Species Specificity; D016597:Trimetrexate / Q000031:analogs & derivatives*
D004338:Drug Combinations; D005965:Glucuronates; D011799:Quinazolines; C056321:trimetrexate glucuronate; D016597:Trimetrexate