       Document 0248
 DOCN  M9620248
 TI    Pharmacokinetics and pharmacodynamics of high-dose zidovudine
       administered as a continuous infusion in patients with cancer.
 DT    9602
 AU    Marchbanks K; Dudley MN; Posner MR; Darnowski J; Department of Pharmacy,
       New Hanover Regional Medical Center,; Wilmington, North Carolina, USA.
 SO    Pharmacotherapy. 1995 Jul-Aug;15(4):451-7. Unique Identifier : AIDSLINE
       MED/96090564
 AB    STUDY OBJECTIVE. To investigate the pharmacokinetics and
       pharmacodynamics of high-dose intravenous zidovudine (ZDV). DESIGN.
       Phase 1, dose-escalating, unblinded study in patients with cancer.
       SETTING. A university-affiliated cancer treatment center. PATIENTS.
       Fourteen patients (6 women) with solid tumors that were unresponsive to
       standard therapy received 31 courses of therapy. INTERVENTIONS.
       Intravenous ZDV was administered in doses of 2, 3, 4, 5.5, 7, 8.5, 10,
       12, 15, or 20 g/m2/day as a continuous infusion over 48 hours. Patients
       also received fluorouracil plus leucovorin for 24 hours before the start
       of and during the ZDV infusion. If no dose-limiting toxicities were
       encountered, subsequent doses were escalated. Blood samples were
       collected at 24 and 48 hours after the start of the infusion, and hourly
       for 4 hours after stopping the infusion. Urine was collected in five
       patients during the infusion and for 24 hours after stopping it. Blood
       for measuring peripheral white blood cells was collected before and at
       the end of the infusion in seven patients to measure DNA chain breaks
       due to incorporation of ZDV. MEASUREMENTS AND MAIN RESULTS. Zidovudine
       was measured in plasma by high-performance liquid chromatography and in
       urine fluorescence polarization immunoassay. Its incorporation into DNA
       was measured by determining DNA strand breakage in peripheral white
       blood cells using fluorescence analysis. Pharmacokinetic models were fit
       to plasma ZDV concentrations using extended least squares regression.
       Short-term high-dose ZDV was generally well tolerated, with adverse
       effects related to large amounts of free water administered during the
       infusion. The mean (SD) ZDV pharmacokinetic values were total clearance
       1.44 (1.09) L/hr/kg, volume of distribution 2.72 (2.97) L/kg, and
       half-life 1.2 (0.6) hours. There was considerable interpatient
       variability in total drug clearance. Although ZDV exposure increased
       proportionately with increasing dose, two of three patients receiving
       the highest dose (20 g/m2/day) had markedly low total drug clearances.
       The relation between the percentage of abnormal DNA in peripheral white
       blood cells and zidovudine area under the plasma ZDV versus time curve
       was described by the Emax pharmacodynamic model. CONCLUSIONS. The
       pharmacokinetics of high-dose ZDV administered by continuous infusion to
       patients with cancer are similar to those reported with lower doses in
       patients with infection due to the human immunodeficiency virus. Further
       study of potential nonlinear pharmacokinetic behavior at doses above 20
       g/m2/day is necessary. The high between-patient variability in ZDV
       clearance results in variable levels of exposure in vivo, and indicates
       the need for concentration- or effect-controlled study designs in the
       further evaluation of the agent's antineoplastic effects.
 DE    Antimetabolites, Antineoplastic/ADMINISTRATION & DOSAGE/
       *PHARMACOKINETICS  Antineoplastic Agents,
       Combined/METABOLISM/THERAPEUTIC USE  Chromatography, High Pressure
       Liquid  Comparative Study  Female  Fluorouracil/METABOLISM/THERAPEUTIC
       USE  Hospitals, University  Human  Infusions, Intravenous
       Leucovorin/METABOLISM/THERAPEUTIC USE  Male  Neoplasms/DRUG
       THERAPY/*METABOLISM  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       P.H.S.  Zidovudine/ADMINISTRATION &
       DOSAGE/PHARMACOLOGY/*PHARMACOKINETICS  CLINICAL TRIAL  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

