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Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1533-1541
A Bioavailability and Pharmacokinetic Study of Oral and
Intravenous Hydroxyurea
By
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.
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ABSTRACT |
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.
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INTRODUCTION |
IN THE MORE THAN three decades since the
ribonucleotide reductase inhibitor hydroxyurea was first evaluated
clinically, a number of diverse applications have been identified for
its use.1-4 Although many of these applications were
identified from the outset, others in both malignant and nonmalignant
diseases are still evolving. The principal use of hydroxyurea has been
as a myelosuppressive agent in the treatment of myeloproliferative
syndromes, particularly chronic myelogenous leukemia and polycythemia
vera.5-8 Although treatment of chronic myelogenous leukemia
with hydroxurea for many years had been reserved for patients whose
disease was no longer responsive to busulfan, hydroxyurea is currently
preferred over busulfan as initial therapy for several
reasons.5-7 First, both initial, uncontrolled studies and
more recent prospective, randomized trials have suggested that
hydroxyurea is more effective than busulfan in prolonging the chronic
phase of the disease and possibly overall survival.5-7
Second, because hydroxyurea has less effect on
hematopoietic stem cells, the prolonged cytopenias that are
occasionally observed with busulfan are noted much less readily with
hydroxyurea. Finally, the leukemogenic potential of hydroxyurea may be
less than that of busulfan.
The use of hydroxyurea as a single agent has never been the mainstay of
treatment for advanced solid tumors; however, recent studies indicate
that the agent might be effective as a biochemical modulator of the
effects of other antimetabolites such as cytosine arabinoside,
fludarabine, and 5-fluorouracil, or DNA-damaging agents such as
etoposide or cisplatin.10-12 There has also been considerable interest in evaluating the potential radiosensitizing properties of hydroxyurea based on its ability to synchronize cells in
radiation-sensitive phases of the cell cycle and inhibit the repair of
radiation-induced DNA damage.12-14 More recently, hydroxyurea has been shown to possess antiviral properties against human immunodeficiency virus type I and to accelerate the loss of
extrachromosomal amplified genes present in double minute
chromosomes.15-17 Treatment of cells in vitro with
clinically achievable drug concentrations results in enhanced loss of
amplified oncogenes and drug resistance genes, and clinical strategies
based on this phenomenon are under consideration.16,17
In the hemoglobinopathies, particularly sickle cell anemia, hydroxyurea
stimulates fetal hemoglobin synthesis, which may be caused, in part, by
inhibition of DNA synthesis in red blood cell progenitors or a specific
alteration of fetal hemoglobin transcription.18-21 In both
pilot studies and a randomized, double-blind multicenter study
involving patients with sickle cell anemia, treatment with hydroxyurea
significantly decreased the incidence of painful sickle cell crises,
thereby establishing it as the first clinically acceptable drug with
activity in this disorder.9,22,23
Hydroxyurea is conventionally administered by the oral route. Although
oral administration has definite advantages in terms of patient
convenience, particularly in situations in which protracted, chronic
low-dose treatment portends optimal biological activity, there have
been concerns about the potential bioavailability of oral hydroxyurea.
However, the bioavailability of oral hydroxyurea has never undergone
rigorous evaluation and quantitation. Most of these concerns
specifically relate to the potential for significant interpatient
variability, limiting the predictability of achieving optimal drug
concentrations to exploit the schedule dependency that has been
observed in preclinical studies.24 For these reasons, an
investigational parenteral formulation of hydroxyurea has been evaluated in patients with advanced malignancies.25-28
However, the comparative pharmacokinetic (PK) characteristics and
bioavailability of intravenous (IV) and oral hydroxyurea have not been
rigorously evaluated despite the widespread use of the agent, and the
relative indications of these formulations are not clear. The principal objectives of this study were to (1) evaluate and quantitate the bioavailability of oral hydroxyurea; (2) characterize the PK behavior of hydroxyurea administered both orally and IV; and (3) assess and
compare the acute toxic effects of both oral and IV hydroxyurea in
patients with advanced solid malignancies.
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MATERIALS AND METHODS |
Eligibility.
Patients with histologically documented, evaluative or measurable solid
tumors refractory to conventional chemotherapy or for whom no effective
therapy existed were candidates for this study. Eligibility criteria
included:
- Age
 18 years.
- A Southwest Oncology Group performance status
 3.
- A life expectancy of at least 12 weeks.
- No radiation therapy and/or chemotherapy within 21 days of
entering onto protocol (42 days if those treated with mitomycin C or a
nitrosourea).
- Adequate hematopoietic (white blood cell [WBC] count 3,000/µL,
absolute neutrophil count [ANC] 1,500/µL, platelets
100,000/µL, and hemoglobin 8 g/dL), hepatic (total bilirubin
1.5 mg/dL; serum glutamic-oxaloacetic transaminase [SGOT] and serum
glutamic-pyruvic transaminase [SGPT] 3-fold times the upper limit
of the institutional normal value) and renal (creatinine 1.5 mg/dL)
functions.
- Serum electrolytes within 10% of upper limit of institutional normal
values, albumin 3.0 g/dL, and glucose 250 mg/dL).
- No evidence of gastrointestinal impairment, atypical frequency of bowel
movements, malignant bowel involvement, or prior surgical excision of
the bowel.
- No other coexisting medical problems of sufficient severity to limit
full compliance with the study.
All patients gave written consent according to federal and
institutional guidelines before treatment.
Study design, dosage, and drug administration.
This randomized crossover design study was designed so that patients
were initially treated with either 2,000 mg of hydroxyurea either
orally or by a 30-minute IV infusion on day 1 of the first course.
Patients fasted 8 hours before and 4 hours after the administration of
oral hydroxyurea. Water was permitted ad lib except for 1 hour prior to
dosing until 15 minutes after drug administration. Coadministration of
oral medications were not permitted during this period in the PK phases
of the study. Blood and urine samples were collected during this study
phase for PK studies. Three days later, all patients continued to
receive hydroxyurea at a dose of 80 mg/kg orally every 3 days for 3 weeks. During the fourth week, the patients did not receive any study
medication. On the fifth week, the patients were crossed over to
receive 2,000 mg of hydroxyurea by the alternate route of
administration, and blood and urine samples were also collected for PK
studies. Three days later, all patients continued taking hydroxyurea at
a dose of 80 mg/kg orally every 3 days for 3 weeks. During the eighth
week, the patients did not receive any study medication. Subsequent
treatment consisted of hydroxyurea administered at a dose of 80 mg/kg
orally every 3 days for at least 6 weeks or until tumor progression was
documented, unacceptable toxicity occurred, or the patient refused
further treatment. Each 6 weeks of maintenance therapy was considered
one complete course. Antacids, H2-histamine antagonists,
prostaglandin inhibitors (eg, misoprostrol), and sucralfate were not
permitted during the PK portions of the trial. Except for day 1 of the
fifth week, at which time oral or IV dosing was to be performed with PK
studies, the dose of hydroxyurea was reduced by 25% if the WBC count
ranged between 2,000/µL and 3,000/µL and/or platelet counts
ranged between 50,000/µL and 100,000/µL on the day of treatment and
treatment was held for WBC counts <2,000/µL and/or platelet
counts <50,000/µL until recovery to WBC count 3,000/µL and
platelet counts 50,000/µL. Toxicity was evaluated according to the
National Cancer Institute (Bethesda, MD), Common Toxicity
Criteria.29
Hydroxyurea was supplied as an oral preparation of 500-mg capsules
commercially available from Bristol Laboratories Oncology Products
(Princeton, NJ). The IV formulation was supplied by the Division of
Cancer Treatment, National Cancer Institute, Bethesda, (MD), as a lyophilized powder in 50-mL vials containing 2 g of hydroxyurea with citric acid (56 mg) and sodium phosphate (144 mg). The
vials were diluted with 18.6 mL of sterile water United States
Pharmacopeia (USP) for injection. The pH of the solution was
6.1. This initial dilution was to be further diluted in
5% dextrose to a total volume of 100 mL and administered over 30 minutes by an infusion pump.
Pretreatment and follow-up studies.
Histories and physical examinations, and routine laboratory studies
were performed pretreatment and weekly after treatment. Laboratory
studies included a complete blood count, differential WBC count,
electrolytes, blood urea nitrogen, creatinine, glucose, total protein,
albumin, calcium, phosphorus, uric acid, alkaline phosphatase, SGOT,
SGPT, total and direct bilirubin, amylase, prothrombin time, and
urinalysis. Twelve-hour urine collections to measure creatinine
clearance and electrocardiograms were also performed pretreatment.
Formal tumor measurements were performed pretreatment and after every
course (every 6 weeks). A complete response was scored if there was
disappearance of all active disease on two measurements separated by at
least 4 weeks, and a partial response required at least a 50%
reduction in the sum of the product of the bidimensional measurements
of all measurable lesions on two measurements separated by at least 4 weeks.
Pharmacological studies.
Extensive plasma sampling after both oral and IV drug administration
was performed in all patients. For blood samples collected in concert
with IV dosing, sampling was performed before treatment, at 15 minutes
during the infusion, and immediately before the end of infusion; plasma
sampling was performed pretreatment and at 15 and 30 minutes after oral
drug administration. For both oral and IV drug administration, plasma
sampling was also performed after the initiation of treatment at the
following times: 36, 45, 90, 120, and 150 minutes; and at 3, 4, 6, 8, 10, 12, and 24 hours. At each sampling time, 1 mL of blood was
withdrawn and then discarded to assure that the heparin solution used
to maintain catheterpatency did not dilute the sample. Then 7 mL of
blood was removed, and the blood sample was centrifuged immediately. A
total of 240 mL of blood was collected over a 2-month period for
bioavailability studies. Plasma, divided into two equal aliquots, were
transferred to plastic tubes, labeled, and kept frozen at  70°C
until analysis. Urine samples were collected before the first dose of
study medication and then continuously over the next 24 hours in pooled
collections of 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours.
Collected urine was shaken to mix thoroughly, and the total volume was
measured and recorded. A 20-mL aliquot was taken, and this was labeled
and kept frozen at 70°C until analysis.
Hydroxyurea concentrations in both plasma and urine samples were
quantitated using a modified colorimetric assay originally described by
Fabricus and Rajewsky.30 Briefly, sample
preparation and analysis were accomplished as follows. A 1-mL plasma
was mixed with 4 mL of water and left to stand for 1 minute. Five
milliliters of 1 mol/L perchloric acid was then added, and after being
left to stand for 10 minutes, the mixture was centrifuged at 10,000 rpm
for 20 minutes at 4°C. The supernatant was then filtered through a
Gelman (Ann Arbor, MI) Nylon Acrodisc (0.45 µm) into clean
polypropylene tubes. For urine, 2 mL of deionized water was used to
dilute a 50-µL aliquot of urine sample. Two milliliters of 1 mol/L
perchloric acid was then added, and after being left to stand for 10 minutes, the mixture was centrifuged at 10,000 rpm for 20 minutes at
4°C. The supernatant was then decanted into clean polypropylene
tubes. For analysis, 2 mL of the standard or sample was added to 1 mL of the working buffer solution (0.5 mol/L
Na2HPO4 + 1.5 mol/L Na2HPO4), 0.1 mL of 10.3 mol/L sodium
hydroxide, 1 mL of 1% sulfanilic acid, and 0.1 mL of 0.1 mol/L iodine
in 2.5% potassium iodide solution. The mixture was left to stand for 1 minute before adding 0.1 mL of freshly prepared aqueous 0.1 mol/L
sodium thiosulfate solution and 1 mL of freshly prepared
naphthylenediamine solution. After leaving the mixture to stand for 20 minutes, the absorbance of the resulting solution was measured in
triplicate at 540 nm on a Beckman DU650 spectrophotometer
(Fullerton, CA) and the average absorbance was recorded.
Hydroxyurea standards for plasma studies were prepared as above in
duplicate at the following concentrations: 0, 15, 20, 40, 60, 100, 200, 400, 600, 800, 1,000, and 1,500 µmol/L. For urine studies,
hydroxyurea standards for generation of the standard curve were 0, 10, 30, 50, 100, 200, 300, and 500 µmol/L. Standard curves for plasma and
urine samples were prepared in duplicate and an average absorbance of
each duplicate sample was read in triplicate and an average absorbance
was recorded. The lower limits of quantitation for the assay were 15 µmol/L and 10 µmol/L for plasma and urine, respectively. The
precision of the assay ranged from 13% at the lower end of the plasma
standard curve to 6.8% at the higher end. The accuracy of the assay,
as assessed as the closeness of the mean value to the theoretical
concentration over the range of the plasma standard curve, was 85.5%
(40 µmol/L), 98.1% (100 µmol/L), and 99.4% (800 µmol/L).
Individual hydroyxurea plasma concentration data from all study
patients were analyzed by both compartmental and noncompartmental methods. The area under the plasma concentration-versus-time curve (AUC) and the area under the first moment-versus-time curve (AUMC) were
calculated using the linear trapezoidal rule. The AUC was extrapolated
to infinity by dividing the last measured concentration by the terminal
rate constant (  ), which was determined using nonlinear least square regression as described below. The systemic clearance (Cl) after IV and oral (Cl/F) administration was calculated by dividing the dose by the AUC. Maximum plasma concentration (Cmax) and time to maximum concentration (Tmax)
following oral administration were determined by inspection of the
concentration-versus-time curve. The mean residence time (MRT) was
determined using the equation, AUMC/AUC (infusion time/2). The mean
transit time (MTT) was calculated by dividing the AUMC by the AUC and
the mean absorption time (MAT) was derived by subtracting the MRT from the MTT. The half-life of absorption (T1/2a) was calculated
by multiplying 0.693 by the MAT. Bioavailability (F) expressed as a
percentage was calculated by dividing the oral AUC by the IV AUC
normalized to dose
(F% = [AUCoral/AUCIV] × [Doseoral/DoseIV, which was equal to 1] × 100%), with the underlying assumption that the drug clearance was the same in each patient during both study
periods, and the dose normalization factor was equal to 1.31 The fraction of hydroxyurea dose excreted in urine
after either IV or oral administration was calculated by dividing the cumulative quantity of hydroxyurea in the urine samples collected over
24 hours by the dose of hydroxyurea (2,000 mg). Renal clearance of
hydroxyurea was estimated by multiplying Cl by the fraction of
hydroxyurea that was excreted in the urine. The volume of distribution (VSS) after the administration of IV and oral hydroxurea
were calculated by the following equations:
{M}where T represents the infusion duration and
Ka is 1/MAT. Clearance and volume of distribution
terms for oral administration were corrected for F.
Plasma concentration-time data were modeled using a nonlinear least
square regression program (RSTRIP [Version 5.0]; Micromath Inc, Salt
Lake City, UT). Concentration data were weighted using 1/concentration2. Goodness of fit of the plasma
concentration-time profiles were determined by visual inspection of the
plasma profiles and also by using the modified Akaike Information
Criteria.32 The oral route model further assumed a
first-order input, with a lag time, and first-order output. The IV
infusion model assumed constant intravenous input over 30 minutes and
first-order output. The secondary pharmacokinetic parameters derived
from fitting the plasma hydroxyurea concentration time profiles to the
linear compartment model included the following: distribution ( )
half-life (T1/2 ), elimination ( ) half-life
(T1/2), the AUC extrapolated to infinity, and the time
delay between drug administration and absorption (Tlag).
The relationships between relevant PK parameters and parameters that
reflected myelosuppression were initially explored by visually
inspecting the scatterplots. Relevant parameters indicative of
myelosuppression that were evaluated included the percentage decrements
in the ANCs and platelet counts, which were calculated as follows: % decrease = 100 × ([pretreatment counts nadir
counts]/pretreatment counts).
Statistical considerations.
PK data are presented as the mean ± SD or range unless otherwise
stated. Ordinary linear regression was used to compare measures of
renal functions and hematopoietic effects with PK parameters for each
individual patient. The nonparametric Wilcoxon signed rank test or
paired Student's t-test was used to compare PK parameters obtained with oral and IV treatment and different orders of
administration.
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RESULTS |
General.
Of the 29 patients who were treated in the study, 15 patients were
randomized to receive oral hydroxyurea as their initial treatment, and
14 patients were randomized to the IV hydroxyurea arm. The
characteristics of these patients are displayed in Table 1. An additional patient was randomized to
the IV hydroxyurea arm, but never received study medication. Two
patients did not meet all eligibility criteria. Both subjects
previously underwent large bowel resections, but it was determined
retrospectively that this deviation neither placed them at increased
risk nor rendered their data invalid for analysis. Mean height and
weight values were 172.9 cm (range, 149.9 to 198) and 74.2 kg (range, 43 to 136.6), respectively. For the bioavailability studies, the single
2,000-mg dose averaged 29.4 mg/kg and 29.7 mg/kg when given orally and
IV, respectively. With few exceptions, the concomitant medications
taken by the patients during the oral and IV portions of the study were
similar. The largest category of concomitant medications was
analgesics, which were taken by 24 patients (83%). Other frequent
categories of concomitant medications included: central nervous system
drugs in 14 patients (48%), endocrine medications in 13 patients
(45%), antianginal or antihypertensive agents in 12 patients (41%),
antihistamines or decongestants in 10 patients (34%), antiemetic or
antidiarrheal medications in 8 patients (28%), diuretics in 7 patients
(24%), and anticoagulants in 3 patients (10%).
There were no objective clinical anti-cancer responses.
Pharmacokinetic studies.
Twenty-two of the 29 patients enrolled in the study
received 2,000 mg hydroxyurea by both oral and IV routes and completed all PK and bioavailability studies. Because of early disease
progression, four patients received oral hydroxyurea only, and three
patients received IV hydroxyurea only. Plasma concentrations from all
of these courses were analyzed by both noncompartmental and
model-dependent methods. The cumulative plasma
concentration-versus-time data for all 22 subjects who were treated
with both oral and IV hydroxyurea are shown in Fig
1. The plasma disposition of hydroxyurea
was well described by a linear two-compartment model with first-order absorption. Hydroxyurea PK parameters and F after IV and oral administration that were determined using both noncompartmental and
compartmental methods are listed in Table
2. Mean AUC values derived using
compartmental methods were in excellent agreement (±10%) with those
obtained using noncompartmental methods.
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| Fig 1.
Plasma concentration-versus-time plots for hydroxyurea
after both oral (PO) and IV administration. The mean (SE)
concentrations as a function of time for all 22 patients are depicted.
(- -), 2 g PO (n = 22); (- -), 2 g IV (n = 22).
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Absorption kinetics.
After oral administration, gastrointestinal absorption was relatively
rapid. The Tmax averaged 1.22 hours and the
Tlag averaged 0.22 hours. The mean
T1/2a oral was 0.53 hours and MAT averaged 0.72 hours. The mean value for Cmax after a 2,000-mg oral
dose of hydroxyurea was 794 µmol/L. The range of AUC values
(noncompartmental) obtained after IV administration of 2,000 mg
hydroyxurea was 2,277 to 5,975 µmol/L/h (mean, 3,552), which was
similar to the AUC range of 2,209 to 4,726 µmol/L/h (mean, 3,934)
after oral administration of hydroxyurea at the same dose.
The order of drug administration (IV v oral as first treatment)
did not affect the PK behavior of hydroxyurea. The mean (±SD) AUC
values for patients receiving oral hydroxyurea as their initial or
second treatment were 3,970 (1,330) and 3,810 (900) µmol/L/h
(P = .63), respectively, whereas comparable values for
patients receiving IV hydroxyurea as their initial or second treatment
were 3,450 (700) and 3,910 (1,530) µmol/L/h (P = .26),
respectively. Based on both noncompartmental and compartmental methods,
the absorption of oral hydroxyurea was high (Table 2). Using
noncompartmental methods, the absolute bioavailability determined from
22 patients averaged 108% (range, 64% to 156%) with an
interindividual coefficient of variation (CV) of 17%. A scatterplot of
the absolute bioavailability values is shown in Fig
2. Bioavailability was approximately 100%
(range, 85% to 127%) in 19 of 22 subjects, whereas bioavailability
was somewhat higher (133% and 156%) in two individuals, and lower (64%) in one subject. No reasonable explanations, including relevant patient characteristics, concomitant medications, or deviation from the
standard drug administration scheme, were evident to account for the
magnitude of variability in the bioavailability of these three
subjects.
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| Fig 2.
Plot absolute oral hydroxyurea bioavailability values for
each individual patient. The line represents the line of identity for
complete (100%) absolute bioavailability.
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Systemic disposition.
The disposition PK parameters of IV and oral hydroxyurea are listed in
Table 2. Individual Cmax values after IV administration averaged 19.5% (20.7%) higher than those achieved after oral
treatment; mean Cmax values were 1,007 and 794 µmol/L,
respectively. Based on compartmental modeling, the initial distribution
phase was short, with harmonic mean values for T1/2iv
and T1/2oral of 0.63 and 1.78 hours, respectively. The
harmonic mean values for the terminal half-lives, T1/2iv
and T1/2oral were nearly identical, 3.39 and 3.32 hours,
respectively. The apparent volumes of distribution VSSiv
and VSSoral/F were 19.71 and 19.65 L/M2,
respectively. The harmonic MRTs for hydroxyurea after IV and oral
administration (MRTiv and MRToral) were 4.79 and 5.45 hours, respectively. Based on noncompartmental methods, the
mean value for IV clearance (Cliv) was 106 mL/min or 72.16 mL/min/M2 when normalized to body-surface area, whereas
oral clearance (Cloral/F) was 124.83 mL/min or 73.16 mL/min/m2.
Urinary excretion.
Sixteen patients had quantitative urine collections for 24 hours after
hydroxyurea administered by both the IV and oral routes. The percentage
of the hydroxyurea dose excreted in urine following IV and oral
treatment averaged 39.2% (range, 21.1 to 62.4%) and 37.8% (range,
26.1% to 45.3%), respectively. The mean (SD) percentages of the total
administered oral dose of hydroxyurea excreted during the three timed
collection intervals (0 to 6, 6 to 12, and 12 to 24 hours) were 23.4%
(7.0), 11.7% (7.0), and 2.9% (11.2), respectively, whereas the
respective percentages excreted in these periods after IV dosing were
29% (11.6), 9.2% (4.8), and 2.9% (2.3). The mean ratio of the
percentages of hydroxyurea excreted in the urine after oral and IV
dosing, another indication of systemic bioavailability, was 0.95 (range, 0.62 to 1.35), with an interindividual CV of 32%. Mean renal
clearance rates were 43.54 mL/min (29.03 mL/min/m2) and
47.83 mL/min (27.15 mL/min/m2) following oral and IV
administration of hydroxyurea, respectively. The renal clearance of
hydroxyurea correlated moderately well with measured creatinine
clearance (r = .55, P < .01). In addition, there
was a moderate inverse relationship between the AUC and renal clearance
of hydroxyurea (r = .59, P < .01).
Toxicity.
The principal toxicity of hydroxyurea administered orally at a dose of
80 mg/kg every 3 days after an initial oral or IV dose of hydroxyurea
at 2,000 mg was myleosuppression, particularly neutropenia.
Thrombocytopenia occurred much less frequently, and severe
thrombocytopenia was uncommon. Only 6 of 29 (19%) patients required
dose modification for hematologic toxicity at any juncture. In this
group that consisted largely of heavily-pretreated subjects, nadir ANC
counts typically occurred in weeks 2 to 4. Neutropenia was not
cumulative, as reflected by a stable incidence of grade 3 or 4 neutropenia with cumulative dosing. The route of administration (oral
or IV) of the first dose of hydroxyurea did not influence the rate or
severity of the various toxicities of hydroxyurea during courses 1 and
2. Overall, 25 of the 29 patients experienced hematologic toxicity of
any severity, including 23 (79%) and 8 (28%) individuals who
developed any grade of neutropenia and thrombocytopenia, respectively.
Sixteen of 29 patients (55%) experienced severe (grade 3 or 4)
myelosuppression sometime in their therapy, with 14 (48%) and 3 (10%)
patients developing grade 3 or 4 neutropenia and thrombocytopenia,
respectively. Of these patients, 6 subjects (19%) experienced grade 4 neutropenia lasting less than 5 days; an ANC nadir <500/µL that
lasted 11 days occurred during a single course administered to one
subject. Fever associated with severe neutropenia requiring treatment
with parenteral antibiotics never occurred. Only 1 (3.4%)
heavily-pretreated individual experienced grade 4 thrombocytopenia of
short duration at the initial dose level of 80 mg/kg and recurrent
thrombocytopenia did not preclude further chronic dosing at a reduced
dose of 60 mg/kg.
Nonhematological effects, possibly attributed to hydroxyurea, occurred
infrequently and were generally mild to modest in severity. The most
common nonhematological toxicity was nausea and/or vomiting, which usually occurred several hours after dosing. Overall, 15 patients
(62%) complained of nausea and 6 patients (21%) experienced vomiting
at some time during the study; however, severe (grade 3) nausea
and/or vomiting occurred in only 3 of 29 patients (10%) and
these toxic effects did not occur during the bioavailability phase of
the study. Nausea and/or vomiting were usually treated successfully with phenothiazines and/or metochlopromide. In
addition, three individuals experienced elevations in their liver
function tests including two patients who developed grade 3 elevations in hepatic transaminases and one subject who developed
hyperbilirubinemia. All of these individuals had liver metastases, but
these effects could not be definitively attributed to disease
progression. One patient developed an atrial arrhythmia during
treatment with hydroxyurea, which resolved after treatment with
digoxin. Other infrequent toxicities that were mild to modest in
severity included diarrhea, anorexia, alopecia, rashes, and malaise.
Pharmacodynamic analysis.
Relationships between hydroxyurea Cmax and AUC and various
parameters indicative of drug effects on neutrophils, including the
percent decrement in ANCs (Fig 3A and B),the ANC nadir (data not shown), and the grade of neutropenia (data not
shown) were sought. Linear relationships were either nonexistent or
very weak (all r values <.3 for Cmax; all
r values <.1 for AUC). In addition, the relationships between
these variables could not be adequately characterized by sigmoidal
maximal effect models.
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| Fig 3.
Scatterplots depicting the percent change in ANC during
course 1 after IV () and oral hydroxyurea ( ) as a function of (A) hydroxyurea Cmax and (B) hydroxyurea AUC.
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| |
DISCUSSION |
The recent resurgence of interest in the use of hydroxyurea in the
therapy of both malignant and nonmalignant diseases has resulted in
concerns about the use of oral administration schedules to simulate
optimal pharmacological conditions required for maximal biological
activity. Another related, albeit unproven, concern is the greater
potential for significant interindividual variability with oral
hydroxyurea, which may also hypothetically preclude achieving optimal
pharmacologic conditions in some clinical settings and individuals. For
these reasons, an investigational parenteral formulation of hydroxyurea
has been made available for evaluations of hydroxyurea on a wide
variety of dose schedules.1 The investigational formulation
has undergone preliminary evaluations, principally on protracted IV
infusion schedules in settings where such a formulation and dosing
schedules might enable achievement and maintenance of
biologically-relevant plasma concentrations, particularly with respect
to modulation of the cytotoxic effects of the antimetabolites, DNA-damaging agents, and radiation.1,2,4,10-12,24-28 Using protracted IV infusion schedules, plasma concentrations in excess of 1 mmol/L have been achieved and maintained for 24 to 72 hours, although
the biological and clinical relevance of this magnitude of drug
concentrations are not known.1,24-28 These concerns
regarding the bioavailability of oral hydroxyurea and the potential for significant interindividual variability with oral dosing, coupled with
a progressively growing interest in the use of the parenteral formulation to alleviate such concerns, served as the impetus for the
present bioavailability and PK study.
In limited preclinical pharmacological studies that were performed
several decades ago involving mice and rats, the bioavailability of
oral hydroxyurea was determined to be 50% and 72%,
respectively.31,33-36 Although the gastrointestinal
absorption of hydroxyurea was evaluated in early clinical studies, the
numbers of patients studied were small, which resulted in a high level
of uncertainty regarding interindividual variability.36-39
In these early studies, oral absorption was usually described
qualitatively as "rapid" and bioavailability as "high," but
pertinent PK and bioavailability parameters were not rigorously
quantitated using conventional, appropriate bioavailability study
designs (ie, randomization between IV and oral drug administration with
subsequent crossover to the alternate treatment). In fact, except for
sporadic reports of individuals who received both oral and IV
hydroxyurea several decades ago, formal bioavailability studies have
not been performed. In a population PK study in which patients with
cancer were treated with a wide range of hydroxyurea dosing schedules,
oral bioavailability was determined to be approximately 79% based on
intergroup comparisons of PK data.33 The investigators
proposed that the lack of complete bioavailability might, in part, be
caused by incomplete drug absorption, gut-wall metabolism,
and/or first-pass metabolism. However, the determination of F
was based on both oral and IV dosing data obtained from different
groups of patients who were treated with either oral or IV hydroxyurea
using widely disparate doses and schedules. For example, eight patients
were treated with oral hydroxyurea at a dose of 20 mmol/m2
(1.5 g/m2) every 6 hours, and PK parameters of IV
hydroxyurea were derived from a different group of patients who were
treated with much higher hydroxyurea doses ranging from 84 to 315 mg/m2/h as a continuous IV infusion for 48 to 72 hours, or
as an unspecified IV loading dose followed by 165 to 950 mg/m2/h as a continuous IV infusion for 24 to 48 hours.
Furthermore, using nonlinear mixed effect modeling, these investigators
determined that the PK behavior of hydroxyurea was nonlinear, which
might have further confounded their calculation of F because patients were treated with high IV hydroxyurea doses that approached the nonlinear spectrum and much lower oral doses. In contrast, the PK
results of a more recent study that evaluated the feasibility of
administering hydroxyurea as a continuous IV infusion for 120 hours at
somewhat lower doses (41 to 133 mg/m2/h) than the
aforementioned doses were similar to those determined in the present
study.40 In that study, the PK behavior of hydroxyurea was
shown to be linear; the mean terminal T1/2 was
3.3 ± 0.2 hour, and ClSS and renal Cl averaged 91.6 ± 5 and 35.6 ± 3 mL/min/m2, respectively, resulting in a mean
renal excretion of 37.2%.
The present study has shown that the bioavailability of oral
hydroxyurea (2,000 mg) is complete or nearly complete. F averaged 108%. Moreover, interindividual variability in F was relatively low,
as indicated by the fact that 19 of 22 individual F values were in a
narrow range of 85% to 127% and the CV value modest at 17%. Overall,
the interindividual variability in bioavailability and other PK
parameters with both IV and oral hydroxyurea were much lower than those
noted with other oral cytotoxic agents such as melphalan, chlorambucil,
busulfan cyclophosphamide, 5-fluorouracil, and
vinorelbine.41-49 For example, the profound interindividual differences in the bioavailability of busulfan results in widely disparate AUCs in individuals undergoing high-dose chemotherapy and
allogeneic bone marrow rescue, which appears to be a critical determinant for both efficacy and toxicity, specifically venoocclusive disease of the liver.47-49 In contrast, the results of the
study discussed in this report indicate that the many apprehensions regarding the potential unpredictability of oral hydroxyurea may be
unfounded. Although the data resulting from a clinically relevant hydroxyurea dose (2,000 mg) was well fit by a two-compartment linear PK
model and this study evaluated one dose level and was not precisely
designed to detect nonlinearity, nonlinear PK behavior has been
appreciated in one retrospective analysis of population PK data from
patients treated with hydroxyurea on multiple dosing schedules.33 In the retrospective population analysis, the
Michealis-Menton constant for hydroxyurea elimination (Km)
was reported to be 0.323 mmol/L, which is in the range of
Cmax values achieved with both IV (mean, 793.75 µmol/L
[range, 503.89 to 1,538.43]) and oral hydroxyurea (mean, 1,006.65 µmol/L [range, 372.54 to 1,279.76]) in the present study.
As indicated by the mean hydroxyurea concentration-time plot depicted
in Fig 1, the PK profiles of oral and IV hydroxyurea were nearly
identical. An exception was the parameter Cmax which was
19.5% (20.7%) higher on average after IV administration. On the other
hand, AUC values achieved with IV and oral hydroxyurea were nearly
identical (r = .81, P < .001). The rates of both
systemic and renal drug clearance with oral and IV drug administration were also very similar, suggesting that the disposition profiles of IV
and oral hydroxyurea are similar, again supporting the notion that the
IV route of administration does not portend significant advantages over
oral dosing schedules. Although the number of reports in the literature
pertaining to the pharmacology of hydroxyurea is scant and the numbers
of patients in these reports are small, the results of these limited PK
and urinary excretion studies concur with the results in the present
study.
The present study also sought to identify pharmacodynamic relationships
between pertinent PK parmeters of hydroxyurea, such as AUC and
Cmax, and indices that reflect the severity of the principal toxicity, neutropenia (eg, ANC nadir, percent decrement in
ANC, and grade of toxicity). Although the design of the study precluded
direct comparisons of the severity of neutropenia and other toxicities
resulting from repetitive treatment of patients with IV and oral
hydroxyurea because only a single IV dose was administered, the acute
toxic effects of oral and IV hydroxyurea were similar. Overall,
pharmacodynamic relationships were not observed. There have been few
pharmacodynamic studies performed with hydroxyurea to date in which
efficacy and/or toxicity were related to PK variables. In one
study involving 32 patients with sickle cell disease who were treated
with a mean daily single oral hydroxyurea dose of 21 mg/kg (range, 10 to 35 mg/kg) for 16 weeks, systemic drug clearance was not useful in
predicting for susceptibility to toxicity.22 In addition,
neither patient age, baseline serum creatinine, nor creatinine
clearance had any bearing on both efficacy and toxicity. However, the
most significant determinants, albeit modest, of the final fetal
hemoglobin level achieved included the last ("steady-state")
plasma hydroxyurea concentration (r = .39,
P = .0001), initial WBC count, and the initial fetal
hemoglobin concentration.
From both PK and bioavailability standpoints, the results of this study
indicate that there are no clear advantages of administering hydroxyurea by the IV route for the most common dosing schedules used
to manage both malignant and benign hematological diseases. In this
large study relative to typical bioavailability studies involving
patients with advanced malignancies who often have multiple coexisting
medical problems and are usually receiving a vast array of concomitant
medications that may affect the gastrointestinal absorption and Cl of
anticancer agents, there was a relatively minor degree of
interindividual variability in the oral bioavailability, as well as the
pharmacological disposition, of both oral and IV hydroxyurea. With the
exception of patients with significantly impaired gastrointestinal
function, there do not appear to be any clear advantages for
administering hydroxyurea parenterally, and clinical evaluations of
novel uses of hydroxyurea, particularly those targeting and maintaining
predefined drug concentrations, should be less wary of using the oral
formulation.
| |
FOOTNOTES |
Submitted August 14, 1997;
accepted October 15, 1997.
Supported in part by National Institutes of Health Grants No.
U01-CA-69853, P30-CA-54174, and M01-RR-0136, the Audie Murphy Veteran's Administration Hospital, and NCI Training Grant No. 5T32-CA09434.
Address reprint requests to Eric K. Rowinsky, MD, The Institute for
Drug Development, Cancer Therapy and Research Center, 8829 Datapoint
Dr, Suite 700, San Antonio, TX 78229.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Donehower RC:
An overview of the clinical experience with hydroxyurea.
Semin Oncol
9:11,
1992
2.
Fishbein WN,
Carbone PP:
Hydroxyurea: Mechanism of action.
Science
142:1069,
1963[Abstract/Free Full Text]
3.
Colvin M,
Bono VH Jr:
The enzymatic reduction of hydroxyurea to urea by mouse liver.
Cancer Res
30:1516,
1970[Abstract/Free Full Text]
4.
Elford HL:
Effect of hydroxyurea on ribonucleotide reductase.
Biochem Biophys Res Commun
33:129,
1968[Medline]
[Order article via Infotrieve]
5.
Kennedy BJ,
Yarbro JW:
Metabolic and therapeutic effects of hydroxyurea in chronic myelogenous leukemia.
JAMA
195:1038,
1966[Abstract/Free Full Text]
6.
Bolin RW,
Robinson WA,
Sutherland J,
Hamman RF:
Busufan versus hydroxyurea in long term therapy of chronic myelogenous leukemia.
Cancer
50:1683,
1982[Medline]
[Order article via Infotrieve]
7. Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK,
Queiber W, Löffler H, Hochhaus A, Heinze B, Georgii A, Bartram
CR, Griebhammer M, Bergmann L, Essers U, Falge C, Queiber U, Meyer P,
Schmitz N, Eimermacher H, Walther F, Fett W, Kleeberg UR, Kabish A,
Nerl C, Zimmerman R, Meuret G, Tichelli A, Kanz L, Tigges F-J, Schmid
L, Brockhaus W, Tobler A, Reiter A, Perker M, Emmerich B, Verpoort K,
Zankovich R, Wussow PV, Prummer O, Thiele J, Buhr T, Carbonell F,
Ansari H, and the German CML Study Group: Randomized comparison of
interferon-alpha with busulfan and hydroxyurea in chronic myelogenous
leukemia. The German CML Study Group. Blood 84:4064, 1994
8.
Sharon R,
Tatarsky I,
Ben-Arieh Y:
Treatment of polycythemia vera with hydroxyurea.
Cancer
57:718,
1986[Medline]
[Order article via Infotrieve]
9.
Rodgers GP,
Dover GJ,
Noguchi CT,
Schecter AN,
Nienhuis AW:
Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea.
N Engl J Med
322:1037,
1990[Abstract]
10.
Ratain MJ,
Schilsky RL,
Wojack BR,
Simon T,
Senekjian EK,
Vogelsang N:
Hydroxyurea and etoposide: In vitro synergy and phase I clinical trial.
J Natl Cancer Inst
80:1412,
1988[Abstract/Free Full Text]
11.
Fram RJ,
Kufe DW:
Inhibition of DNA excision repair and the repair of x-ray-induced DNA damage by cytosine arabinoside and hydroxyurea.
Pharmacol Ther
31:165,
1985[Medline]
[Order article via Infotrieve]
12.
Schilsky RL,
Ratain MJ,
Vokes EE,
Vogelsang NJ,
Anderson J,
Peterson BA:
Laboratory and clinical studies of biochemical modulation by hydroxyurea.
Semin Oncol
19:84,
1992[Medline]
[Order article via Infotrieve]
13.
Fram RJ,
Kuge DW:
Effect of 1-D-beta arabinofuranosyl cytosine and hydroxyurea on the repair of x-ray induced DNA single strand breaks in human leukemia blasts.
Biochem Pharmacol
34:2557,
1985[Medline]
[Order article via Infotrieve]
14.
Stehman FB,
Bundy BN,
Thomas G,
Keys HM,
d'Ablaing G III,
Fowler WC Jr,
Mortel R,
Creasman WT:
Hydroyxurea versus misonidazole with radiation in cervical carcinoma: Long-term follow-up of a Gynecologic Oncology Group trial.
J Clin Oncol
11:1523,
1993[Abstract/Free Full Text]
15.
Lori F,
Malykh A,
Cara A,
Sun D,
Weinstein JN,
Lisziewicz J,
Gallo RC:
Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication.
Science
266:801,
1994[Abstract/Free Full Text]
16.
Von Hoff DD,
Waddelow T,
Forseth B,
Davidson K,
Scott J,
Wahl G:
Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells.
Cancer Res
51:6273,
1991[Abstract/Free Full Text]
17.
Eckhardt SG,
Dai A,
Davidson KK,
Forseth BJ,
Wahl GM,
Von Hoff D:
Induction of differentiation in HL-60 cells by the reduction of extrachromosomally-amplified c-myc.
Proc Natl Acad Sci USA
91:6674,
1994[Abstract/Free Full Text]
18.
Dover GJ,
Charache S,
Nora R,
Boyer SH:
Progress toward increasing fetal hemoglobin production in man: Experience with 5-azacytidine and hydroxyurea.
Ann NY Acad Sci
445:218,
1985[Medline]
[Order article via Infotrieve]
19.
Miller BA,
Platt O,
Hope S,
Nathan DG:
Influence of hydroxyurea on fetal hemoglobin production in vitro.
Blood
70:1824,
1987[Abstract/Free Full Text]
20.
Galanello R,
Stamatoyannopoulos G,
Papayannopoulou T:
Mechanism of Hb F stimulation by S-stage compounds: In vitro studies with bone marrow cells exposed to 5-azacytidine, ARA-C or hydroxyurea.
J Clin Invest
81:1209,
1988
21.
Ballas SK,
Dover GJ,
Charache S:
Effect of hydroxyurea on the rheological properties of sickle erthrocytes in vivo.
Am J Hematol
32:104,
1989[Medline]
[Order article via Infotrieve]
22.
Charache S,
Dover GJ,
Mover MA,
Moore JW:
Hydroxyurea induced augmentation of fetal hemoglobin production in patients with sickle cell anemia.
Blood
69:109,
1987[Abstract/Free Full Text]
23.
Charache S,
Dover GJ,
Moore RD,
Eckert S,
Ballas SK,
Koshy M,
Milner PFA,
Orringer EP,
Phillips G Jr,
Platt OS,
Thomas GH:
Hydroxyurea: Effects on hemoglobin F production in patients with sickle cell anemia.
Blood
79:2555,
1992[Abstract/Free Full Text]
24.
Brockman RW,
Shaddix S,
Laster WR Jr,
Schabel FM Jr:
Inhibition of ribonucleotide reductase. DNA synthesis and L1210 leukemia by guanazole.
Cancer Res
30:2358,
1960[Abstract/Free Full Text]
25.
Belt RJ,
Haas CD,
Kennedy J,
Taylor S:
Studies of hydroxyurea administered by continuous infusion. Toxicity, pharmacokinetics, and cell syncronization.
Cancer
46:455,
1980[Medline]
[Order article via Infotrieve]
26.
Veale D,
Cantwell BMJ,
Kerr N,
Upfold A,
Harris AL:
Phase I study of high-dose hydroxyurea in lung cancer.
Cancer Chemother Pharmacol
21:53,
1988[Medline]
[Order article via Infotrieve]
27.
Vaughan WP,
Kris E,
Vose J,
Bierman PJ,
Gwilt P,
Armitage JO:
Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.
J Clin Oncol
13:1089,
1995[Abstract]
28.
Tracewell WG,
Trump DL,
Vaughan WP,
Smith DC,
Gwilt PR:
Population pharmacokinetics of hydroxyurea in cancer patients.
Cancer Chemother Pharacol
35:417,
1995[Medline]
[Order article via Infotrieve]
29. Division of Cancer Treatment, National Cancer Institute:
Guidelines for reporting of adverse drug reactions. Bethesda, MD,
National Cancer Institute, 1988
30.
Fabricus E,
Rajewsky MF:
Determination of hydroxyurea in mammalian tissues and blood.
Rev Eur Etudes Clin Biol
16:679,
1971[Medline]
[Order article via Infotrieve]
31. Gibaldi M, Perrier D: Pharmacokinetics (ed 2). New York, NY,
Dekker, 1982
32.
Yamaoka K,
Nakagaawa T,
Uno T:
Application of Akaike's information criteria (AIC) in the evaluation of linear pharmacokinetic equations.
J Pharmacokinet Biopharm
6:165,
1978[Medline]
[Order article via Infotrieve]
33.
Tracewell WG,
Vaughan WP,
Gwilt PR:
Nonlinear disposition of hydroxyurea.
J Pharm Sci
83:1060,
1994[Medline]
[Order article via Infotrieve]
34. (suppl)
Tracewell WG,
Vaughan WP,
Gwilt P:
Pharmacokinetics of hydroxyura in the rat.
Pharm Res
9:S260,
1992
35.
Adamson RH,
Ague SL,
Hess SM,
Davidson JD:
The distribution, excretion, and metabolism of hydroxyurea-14C.
J Pharmacol Exp Ther
150:322,
1965[Abstract/Free Full Text]
36.
Rosner F,
Rubin H,
Parise F:
Studies on the absorption, distribution, and excretion of hydroxyurea (NSC-32065).
Cancer Chemother Rep
55:167,
1971[Medline]
[Order article via Infotrieve]
37.
Bolton BH,
Woods LA,
Kaung DT,
Lawton RL:
A simple method of colorimetric analysis for hydroxyurea (NSC-32065).
Cancer Chemother Rep
46:1,
1965
38. Davidson JD, Winters TS: A method of analyzing for hydroxyurea
in biological fluids. Cancer Chemother rep 27:97, 1963
39. Beckloff GL, Lerner HJ, Frost D, Russo-Alesi, Gitomer S:
Hydroxyurea (NSC-32065) in biologic fluids: Dose-concentration relationship. Cancer Chemother Rep 48:57, 1965
40.
Newman EM,
Carroll M,
Akman SA,
Chow W,
Coluzzi P,
Hamasaki V,
Leong LA,
Margolin KA,
Morgan RJ,
Raschko JW,
Shibata S,
Somlo G,
Tetef M,
Yen Y,
Ahn CW,
Doroshow JH:
Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors.
Cancer Chemother Pharmacol
39:254,
1997[Medline]
[Order article via Infotrieve]
41.
Tattersall MHN,
Jarman M,
Newlands S,
Holyhead L,
Milstead AV,
Weinberg A:
Pharmacokinetics of melphalan following oral or intravenous administration in patients with malignant disease.
Eur J Cancer
14:507,
1978
42. (suppl 6)
McLean A,
Woods RC,
Catovsky D,
Farmer P:
Pharmacokinetics and metabolism of chlorambucil in man. A preliminary report.
Cancer Treat Rev
6:33,
1979
43.
Sladak NE,
Doeden D,
Powers JF,
Krivit W:
Plasma concentrations of 4-hydroxycyclophosphamide and phosporamide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation.
Cancer Treat Rep
68:1247,
1984[Medline]
[Order article via Infotrieve]
44.
Struck RF,
Alberts DS,
Horne K,
Philips JG,
Peng Y-M,
Roe DJ:
Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial.
Cancer Res
47:2723,
1987[Abstract/Free Full Text]
45.
Diasio RB,
Harris BE:
Clinical pharmacology of 5-fluorouracil.
Clin Pharmacokinet
16:215,
1989[Medline]
[Order article via Infotrieve]
46.
Rowinsky EK,
Noe DA,
Trump DL,
Winer EP,
Lucas VS,
Wargin WA,
Hohnecker JA,
Lubejko B,
Sartorius S,
Ettinger D,
Donehower RC:
Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors.
J Clin Oncol
12:1754,
1994[Abstract/Free Full Text]
47.
Jones RJ,
Piantadosi S,
Mann RB,
Ambinder RF,
Seifter EJ,
Vriesendorp HM,
Abeloff MD,
Burns WH,
May WS,
Rowley SD,
Vogelsang GB,
Wagner JE,
Wiley JM,
Wingard JR,
Yeager AM,
Saral R,
Santos G:
High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease.
J Clin Oncol
8:527,
1990[Abstract]
48.
Grochow LB:
Pharmacokinetics of busulfan in preparative regimens for bone marrow transplantation.
Semin Oncol
10:18,
1993
49.
Yeager AM,
Wagner JE,
Graham ML,
Jones RJ,
Santos GW,
Grochow LB:
Optimization of busulfan dosage in children undergoing bone marrow transplantation: A pharmacokinetic study of dose escalation.
Blood
80:2425,
1992[Abstract/Free Full Text]
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Abstract
Introduction
Abstract
![V<SUB>SS</SUB>(oral) = F[(AUMC) × Dose/AUC<SUP>2</SUP>) − (Dose/K<SUB>a</SUB> × AUC)]](/content/vol91/issue5/fulltext/1533/img002.gif)