ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 2000, p. 1100–1101 Vol. 44, No. 4
Effect of Fluconazole on the Pharmacokinetics of Doxorubicin
in Nonhuman Primates
KATHERINE E. WARREN,* CYNTHIA M. MCCULLY, THOMAS J. WALSH, AND FRANK M. BALIS
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892-1928
Received 26 February 1999/Returned for modiﬁcation 23 December 1999/Accepted 18 January 2000
Antifungal prophylaxis in cancer patients who are undergoing chemotherapy is associated with prolonged
neutropenia. We measured the effect of ﬂuconazole on doxorubicin pharmacokinetics in nonhuman primates
to determine if neutropenia is related to a pharmacokinetic interaction that delays the clearance of the
chemotherapeutic agent. Fluconazole pretreatment had no effect on doxorubicin pharmacokinetics.
Dose-intensive anticancer chemotherapy regimens are asso- 48 h after the end of the infusion. Plasma was separated im-
ciated with prolonged neutropenia and an increased risk of mediately by centrifugation and frozen at 70°C until assayed.
fungal infections. Although the routine use of antifungal Doxorubicin (Rubex; Chiron Therapeutics, Emeryville, Cal-
prophylaxis in this patient population remains controversial, if.) at a dose of 2.0 mg/kg was administered intravenously (i.v.)
ﬂuconazole appears to prevent mucosal and disseminated can- over 60 min, alone and after ﬂuconazole, using a randomized
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didiasis in bone marrow transplant recipients (4, 15). The lim- crossover design. Studies using the same animal were separat-
itations of prophylactic antifungal therapy include an increased ed by 2 to 4.5 months. Fluconazole (10 mg/kg/day) was given
risk of resistant fungal infections and a higher incidence of i.v. over 30 min daily for the 3 days prior to doxorubicin, and
bacterial infections (14). In addition, in randomized clinical a fourth dose was administered 2 h prior to doxorubicin. Flu-
trials with adult patients who received dose-intensive antican- conazole was not continued after the doxorubicin dose, be-
cer chemotherapy, antifungal prophylaxis with ketoconazole or cause it has a long t1/2 (25 h in nonhuman primates, 31.6 4 h
ﬂuconazole was associated with prolongation of chemothera- in humans), which results in prolonged drug exposure (2, 3).
py-induced, severe neutropenia (9, 12). The mechanism of this Complete blood counts and chemistries were performed on the
prolonged neutropenia was not identiﬁed. animals twice weekly for at least 4 weeks after drug adminis-
The triazole antifungal agent ﬂuconazole and the imidazole tration.
ketoconazole inhibit hepatic cytochrome P450 enzymes, and Doxorubicin concentrations in plasma were measured with a
these agents are known to alter the clearance of a variety drugs reverse-phase high-performance liquid chromatography meth-
(1). Doxorubicin is a myelosuppressive anticancer drug that is od using ﬂuorescence detection. Daunorubicin served as an
frequently incorporated into combination dose-intensive treat- internal standard. Plasma samples were prepared by solid-
ment regimens for a variety of solid tumors and acute leuke-
mias. The pharmacokinetics of doxorubicin is characterized by
an initial rapid tissue distribution phase (half-life [t1/2], 10
min), followed by a prolonged elimination phase [t1/2, 30 h) (5,
11, 13). Although the plasma doxorubicin concentration at the
start of the elimination phase is only 2% of the peak plasma
drug concentration, 75% of the total drug exposure is ac-
counted for during the elimination phase (5). Doxorubicin is
eliminated by hepatic metabolism and biliary excretion (11),
and drugs that inhibit or induce hepatic drug-metabolizing
enzyme systems, such as ranitidine (6) and phenobarbital (10),
can alter the clearance of doxorubicin. We hypothesized that
the prolonged neutropenia associated with ﬂuconazole pro-
phylaxis in patients with hematological malignancies may be
due to delayed clearance of doxorubicin.
Four adult male rhesus monkeys (Macaca mulatta) ranging
in weight from 7.1 to 12.7 kg were used in this study (7). The
animals were group housed in accordance with the Guide for
the Care and Use of Laboratory Animals (8) and received food
and water ad libitum. Heparinized blood samples were drawn
from a saphenous or femoral venous catheter (contralateral to
the site of drug injection) prior to infusion of doxorubicin, 30
min after the start of the infusion, at the end of the infusion,
and 5, 10, 15, 30, 60, and 90 min and 2, 3, 4, 6, 8, 10, 24, and
* Corresponding author. Mailing address: Pediatric Oncology Branch, FIG. 1. Plasma concentratoin-time proﬁle of doxorubicin (2 mg/kg) admin-
Bldg. 10/Rm. 13N240, 10 Center Dr., MSC 1928, Bethesda, MD 20892- istered i.v. over 60 min alone (E) and after 4 days of ﬂuconazole ( ). The values
1928. Phone: (301) 496-1756. Fax: (301) 402-0575. E-mail: warrenk shown are geometric means for four animals. The mean CV for doxorubicin
@exchange.nih.gov. alone was 33.6%; the mean CV for doxorubicin with ﬂuconazole was 57%.
VOL. 44, 2000 NOTES 1101
TABLE 1. Doxorubicin pharmacokinetic parameters The incidence of severe neutropenia (absolute neutrophil
in nonhuman primatesa count of 500/ l) was higher with doxorubicin alone (three
AUC Clearance Vss animals) than with the combination of doxorubicin and ﬂucon-
t1/2 (h)c azole (zero animals). The prolongation of chemotherapy-in-
Monkey (nM h) (liters/h/kg) (liters/kg)b
duced neutropenia associated with prophylactic ﬂuconazole
does not appear to be related to a pharmacokinetic interaction
RQ293 2,540 1,450 1.4 2.4 55 21 46 19 with doxorubicin.
88003 1,970 2,220 1.7 1.5 17 20 14 15
R838A 1,960 3,040 1.8 1.1 11 14 12 16
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