Pharmacokinetic and phase I evaluation of esorubicin (4'-deoxydoxorubicin) by continuous infusion over forty-eight hours in patients with leukemia.
Sixteen patients with previously treated acute nonlymphocytic leukemia or chronic myelogenous leukemia in blast crisis were given one to three courses of esorubicin by continuous infusion over 48 h. Dosage levels extended from 35 to 85 mg/m2. Four patients showed partial responses of short duration. Nonhematological toxicity observed at dosages of 55 to 85 mg/m2 were mucositis, diarrhea, skin rash, transaminitis, nausea, vomiting, and cardiac dysfunction. One patient receiving 85 mg/m2 developed acute florid congestive heart failure within hours of administration of the drug. Pharmacokinetic analysis revealed large interpatient variation in plasma drug levels. At the end of infusion, plasma decay of esorubicin was rapid initially but slow thereafter, with a terminal half-life of 20 to 54 h. The metabolite 4'-deoxy-13-hydroxydoxorubicin reached significant plasma levels. Total body clearance, renal clearance, volume of distribution at steady state, and mean residence time show little variation during dose escalation for both esorubicin and 4'-deoxy-13-hydroxydoxorubicin. Urinary excretion of esorubicin and 4'-deoxy-13-hydroxydoxorubicin accounted for 10.5 and 1.5%, respectively, of the administered dose.
Kreis
W
W
Department of Medicine, North Shore University Hospital, Manhasset, New York.
Rottach
C
C
Budman
D R
DR
Chan
K
K
Schulman
P
P
Allen
S L
SL
Weiselberg
L
L
Vinciguerra
V
V
D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007938:Leukemia / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate
D004317:Doxorubicin; C030851:esorubicin