title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Bauer
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Tushar S
authors.initials: TS
authors.lastname: Garimella
authors.forename: Suhlan
authors.initials: S
authors.lastname: Wu
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Ross
mesh_terms: 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
chemical_list: D003524:Cyclosporins; D003561:Cytarabine; D005047:Etoposide; C070272:valspodar; D015255:Idarubicin