Pharmacology of chronic oral daily administration of idarubicin.
Idarubicin (4-demethoxydaunorubicin) (IDA) is a daunorubicin analogue with substantial activity in hematologic malignancies and solid tumors. Among several reasons, IDA is of interest because of its main metabolite derivative, the C-13 alcohol analogue, idarubicinol (IDOL). Previous studies have suggested that IDOL, unlike other anthracycline metabolic derivatives, possesses a striking growth-inhibitory activity in tumor cell lines. This suggests that IDOL, like IDA could be useful in circumventing MDR. IDA is bioavailable in an oral dosage form. After oral administration of IDA to the patients, the concentration of IDOL quickly exceeds that of IDA and is retained in the plasma for a longer period. Hence, administration of IDA to cancer patients results ina much greater overall exposure of the tumor to IDOL than to the parent compound. At the Oncology Center (CRO) in Aviano we performed a dose-finding and pharmacokinetic (PK) study of chronic daily oral IDA with intrapatient escalation in patients with metastatic breast cancer (MBC). All the patients were pretreated with anthracyclines (the cumulative dose was 530 mg and 264 mg, respectively, for epirubicin and (DOX) and had at admittance a PS < or = 2 and a left ventricular ejection fraction > 50%. IDA (1 mg capsules) was administered orally twice a day for 21 days every two weeks. Treatment was continued at escalating doses until progression or intolerance. Twenty-five patients were enrolled. MTD has not yet been reached and clinical results are reported in Table 1. Treatment was well-tolerated in all but one patient (300 ANC at day 28). Three patients had tox G3 ANC for more than three weeks after 3, 6, and 7 mg doses, respectively. Two of them stopped chemotherapy after 1 cycle and 1 patient stopped after 2 cycles (6 mg doses). Despite previous treatments with anthracyclines (the mean cumulative dose before entering the study was 530 and 264 mg, respectively, for epirubicin and DOX) no cardiotoxicity due to IDA treatment was observed. This trial demonstrates the feasibility of chronic daily IDA administration. At the dosage reported, treatment was generally well tolerated. The PK findings (high IDOL concentrations) and the unexpected G4 myelotoxicity in patients with the highest IDOL plasma concentrations suggest that IDOL is clinically relevant.
Toffoli
G
G
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Sorio
R
R
Aita
P
P
Crivellari
D
D
Corona
G
G
Rimondi
G
G
Bearz
A
A
Stocco
F
F
Robieux
I
I
Boiocchi
M
M
D000284:Administration, Oral; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D015255:Idarubicin