Effect of Fluconazole on the Pharmacokinetics of Doxorubicin in

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					ANTIMICROBIAL AGENTS    AND   CHEMOTHERAPY, Apr. 2000, p. 1100–1101                                                                            Vol. 44, No. 4
0066-4804/00/$04.00 0

         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
B9078         2,030      1,940      1.7      1.8     13      23      6.8      19                                     REFERENCES
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