Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.
OBJECTIVE
Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS).


METHODS
Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks. Selected KS and solid-tumor patients underwent pharmacokinetic evaluation.


RESULTS
The area under the plasma concentration curve (AUC) ranged from 16.9 micrograms.h/mL to 375.3 micrograms./mL and the alpha half-life ranged from 7.8 to 8.3 hours at 10 mg/m2 to 60 mg/m2, respectively. Both pharmacokinetic profiles were significantly better compared with free daunorubicin. DaunoXome was well tolerated with no significant alopecia, mucositis, or vomiting. Neutropenia (< 1,000/microL occurred in 17% of cycles and was severe (< 500/microL) in only 2%. Anemia and thrombocytopenia were uncommon. Other adverse events included mild to moderate fatigue, nausea, and diarrhea. Even after cumulative doses greater than 1,000 mg/m2, no significant declines in cardiac function were observed. Twenty-two patients who received 50 and 60 mg/m2 were assessable for tumor response; 12 (55%) had a partial response (PR) or clinical complete response (CR). The median survival duration in all patients was 9 months. Prognostic factors for short survival were low CD4 lymphocyte counts (P = .004) and prior anthracycline therapy (P = .02).


CONCLUSIONS
DaunoXome has an improved pharmacokinetic profile compared with free daunorubicin, and is well tolerated. DaunoXome can be given safely at doses up to 60 mg/m2 every 2 weeks and has significant antitumor activity in patients with AIDS-KS.
Gill
P S
PS
Department of Medicine, Kenneth Norris Cancer Hospital and Research Institute, University of Southern California School of Medicine, Los Angeles 90033, USA.
Espina
B M
BM
Muggia
F
F
Cabriales
S
S
Tulpule
A
A
Esplin
J A
JA
Liebman
H A
HA
Forssen
E
E
Ross
M E
ME
Levine
A M
AM
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000328:Adult; D015331:Cohort Studies; D003630:Daunorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004337:Drug Carriers; D005260:Female; D006207:Half-Life; D006801:Humans; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011379:Prognosis; D012074:Remission Induction; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D015996:Survival Rate
D004337:Drug Carriers; D008081:Liposomes; D003630:Daunorubicin