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A Bioavailability and Pharmacokinetic Study of Oral and
Intravenous Hydroxyurea
Gladys I. Rodriguez,
John G. Kuhn,
Geoffrey R. Weiss,
Susan G. Hilsenbeck,
John R. Eckardt,
Allison Thurman,
David A. Rinaldi,
Stephanie Hodges,
Daniel D. Von Hoff, and
Eric K. Rowinsky
From the Institute for Drug Development, Cancer Therapy and Research
Center; and The University of Texas Health Science Center, San Antonio,
TX.
Despite the widespread usage of hydroxyurea in the treatment of both
malignant and nonmalignant diseases and a recent expansion in the
recognition of its potential therapeutic applications, there have been
few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior
and oral bioavailability. Parenteral administration schedules have been
evaluated because of concerns about the possibility for significant
interindividual variability in the PK behavior and bioavailability of
hydroxyurea after oral administration. In this PK and bioavailability
study, 29 patients with advanced solid malignancies were randomized to
treatment with 2,000 mg hydroxyurea administered either orally or as a
30-minute intravenous (IV) infusion accompanied by extensive plasma and
urine sampling for PK studies. After 3 weeks of treatment with
hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout
period), patients were crossed over to the alternate route of
administration, at which time extensive PK studies were repeated. Three
days later, patients continued treatment with 80 mg/kg hydroxyurea
orally every 3 days for 3 weeks, followed by a 1-week rest period.
Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days.
Twenty-two of 29 patients had extensive plasma and urine sampling
performed after treatment with both oral and IV hydroxyurea. Oral
bioavailability (F) averaged 108%. Moreover, interindividual
variability in F was low, as indicated by 19 of 22 individual F values
within a narrow range of 85% to 127% and a modest coefficient of
variation of 17%. The time in which maximum plasma concentrations
(Cmax) were achieved averaged 1.22 hours with an average
lag time of 0.22 hours after oral administration. Except for
Cmax, which was 19.5% higher after IV drug administration,
the PK profiles of oral and IV hydroxyurea were very similar. The
plasma disposition of hydroxyurea was well described by a linear
two-compartment model. The initial harmonic mean half-lives for oral
and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the
harmonic mean terminal half-lives were 3.32 and 3.39 hours,
respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at
steady-state was 19.71 L/m2, whereas
Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after
oral administration. The percentage of the administered dose of
hydroxyurea that was excreted unchanged into the urine was nearly
identical after oral and IV administration 36.84% and 35.82%,
respectively. Additionally, the acute toxic effects of hydroxyurea
after treatment on both routes were similar. Relationships between
pertinent PK parameters and the principal toxicity, neutropenia, were
sought, but no pharmacodynamic relationships were evident. From PK,
bioavailability, and toxicologic standpoints, these results indicate
that there are no clear advantages for administering hydroxyurea by the
IV route except in situations when oral administration is not possible
and/or in the case of severe gastrointestinal impairment.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1533-1541
© 1998 by The American Society of Hematology.
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