Despite the widespread usage of hydroxyurea in the treatment of both m
alignant and nonmalignant diseases and a recent expansion in the recog
nition of its potential therapeutic applications, there have been few
detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and or
al bioavailability. Parenteral administration schedules have been eval
uated because of concerns about the possibility for significant interi
ndividual variability in the PK behavior and bioavailability of hydrox
yurea after oral administration. In this PK and bioavailability study,
29 patients with advanced solid malignancies were randomized to treat
ment with 2,000 mg hydroxyurea administered either orally or as a 30-m
inute intravenous (IV) infusion accompanied by extensive plasma and ur
ine sampling for PK studies. After 3 weeks of treatment with hydroxyur
ea (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, pa
tients continued treatment with 80 mg/kg hydroxyurea orally every 3 da
ys 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 pa
tients had extensive plasma and urine sampling performed after treatme
nt with both oral and IV hydroxyurea. Oral bioavailability (F) average
d 108%. Moreover, interindividual variability in F was low, as indicat
ed 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 maxi
mum plasma concentrations (C-max) were achieved averaged 1.22 hours wi
th an average lag time of 0.22 hours after oral administration. Except
for C-max, which was 19.5% higher after IV drug administration, the P
K profiles of oral and IV hydroxyurea were very similar. The plasma di
sposition of hydroxyurea was well described by a linear two-compartmen
t model. The initial harmonic mean half-lives for oral and IV hydroxyu
rea were 1.78 and 0.63 hours, respectively, and the harmonic mean term
inal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxy
urea, systemic clearance averaged 76.16 mL/min/m(2) and the mean volum
e of distribution at steady-state was 19.71 L/m(2), whereas Cl-oral/F
and V-oral/F averaged 73.16 mL/min/m(2) and 19.65 L/m(2), respectively
, after oral administration. The percentage of the administered dose o
f hydroxyurea that was excreted unchanged into the urine was nearly id
entical after oral and IV administration-36.84% and 35.82%, respective
ly. Additionally, the acute toxic effects of hydroxyurea after treatme
nt on both routes were similar. Relationships between pertinent PK par
ameters and the principal toxicity, neutropenia, were sought, but no p
harmacodynamic relationships were evident. From PK, bioavailability, a
nd toxicologic standpoints, these results indicate that there are no c
lear advantages for administering hydroxyurea by the IV route except i
n situations when oral administration is not possible and/or in the ca
se of severe gastrointestinal impairment. (C) 1998 by The American Soc
iety of Hematology.