A phase I and pharmacologic study of idarubicin, cytarabine, etoposide, and the multidrug resistance protein (MDR1/Pgp) inhibitor PSC-833 in patients with refractory leukemia.
This study was conducted to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and pharmacokinetics of idarubicin when administered with and without the P-glycoprotein inhibitor PSC-833 in combination with cytarabine, and etoposide. Fifteen patients with relapsed and refractory acute leukemia were enrolled and received cytarabine as a 7-day continuous infusion, with etoposide and idarubicin administered for any three consecutive days during the cytarabine infusion. Two hours prior to the second dose of idarubicin, PSC-833 administration was initiated. The pharmacokinetics of idarubicin alone and with PSC-833 was assessed at three idarubicin dose levels (6, 8 and 10 mg/m(2)). The MTD of idarubicin in this combination was 8 mg/(m(2) day) with a DLT of oral mucositis. The complete remission rate (on an intent-to-treat basis) for this regimen was 33%, with a median duration of 6 months. The clearance of idarubicin was 140 +/- 200 and 181 +/- 94.3 l/h for idarubicin alone and with PSC-833, respectively. The volume of distribution of the central compartment was 423 +/- 443 and 337 +/- 394 l for idarubicin alone and in combination with PSC-833, respectively. This combination including PSC-833 was well tolerated. Although a pharmacokinetic interaction might have been expected, PSC-833 did not significantly alter the disposition of idarubicin.
Bauer
Kenneth S
KS
Greenebaum Cancer Center, University of Maryland School of Pharmacy, Allied Health Building Suite 540, 100 Penn Street, Baltimore, MD 21201, USA. kbauer@rx.umaryland.edu
Karp
Judith E
JE
Garimella
Tushar S
TS
Wu
Suhlan
S
Tan
Ming
M
Ross
Douglas D
DD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003524:Cyclosporins / Q000008:administration & dosage / Q000493:pharmacokinetics; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016896:Treatment Outcome
D003524:Cyclosporins; D003561:Cytarabine; D005047:Etoposide; C070272:valspodar; D015255:Idarubicin