Kidney International, Vol. 61 (2002), pp.
1495–1501
Cyclophosphamide pharmacokinetics and dose requirements in
patients with renal insufficiency
MARION HAUBITZ, FRANK BOHNENSTENGEL, REINHARD BRUNKHORST, MATTHIAS SCHWAB,
UTE HOFMANN, and DAGMAR BUSSE
Department of Nephrology, University Medical School Hannover, Hannover, and Dr. Margarete Fischer-Bosch-Institute of
Clinical Pharmacology, Stuttgart, Germany
Cyclophosphamide pharmacokinetics and dose requirements
in patients with renal insufficiency.
Background: Intravenous pulse administration of cyclophos-
phamide (CYC) has been successfully used for the treatment of
various autoimmune diseases. These patients often present with
impaired renal function or even end-stage renal failure. Never-
theless, data concerning pharmacokinetics of CYC in renal in-
sufficiency (RI) and on hemodialysis (HD) are rare and con-
tradictory.
Methods: The pharmacokinetics of CYC (0.5 to 1 g/m2 as a
one-hour infusion) were determined in patients with renal in-
volvement of autoimmune diseases. Group A (N ⫽ 6) patients
had a creatinine clearance (CCr) of 25 to 50 mL/min, group B
patients’ (N ⫽ 5) CCr was 10 to 24 mL/min, and group C (N ⫽
6) patients had CCr values ⬍10 mL/min and HD. Concentrations
of CYC in serum, dialysate and urine were measured by HPLC.
Twelve previously investigated patients with normal renal func-
tion served as controls.
Results: Mean clearance (CL) of CYC was significantly re-
duced with decreased renal function (79 vs. 57 and 47 mL/min,
controls vs. A and B, respectively, P ⬍ 0.05), but only moderately
lower in the patients who received a three-hour HD during the
study period (group C, 64 mL/min, NS). This resulted in re-
ciprocal increases in systemic drug exposure (dose corrected
AUC was 216, 298, 382 and 266 ␮g · h/mL · g, controls, A, B
and C, respectively). Urinary excretion of CYC was markedly
reduced in all patients with RI (renal CL was 14.9 vs. 3.4, 2.4
and 2.1 mL/min, controls vs. A, B and C, respectively, P ⬍
0.001). However, in patient group C, a mean of 22% of adminis-
tered CYC dose was eliminated by a three hour HD starting
seven hours after CYC administration. Individual CCr values
were significantly (P ⬍ 0.001) correlated with renal and sys-
temic CL of CYC, respectively, and negatively correlated with
dose corrected AUC.
Conclusions: Clearance of CYC is decreased in patients with
reduced renal function, thereby resulting in an increased sys-
temic drug exposure. However, in hemodialysis-dependent pa-
tients, removal of CYC into the dialysate has to be taken into
Key words: renal insufficiency, hemodialysis, intravenous pulse ther-
apy, immunosuppression, cytotoxicity, systemic lupus erythematosus.
Received for publication August 29, 2001
and in revised form November 12, 2001
Accepted for publication November 15, 2001
 2002 by the International Society of Nephrology
1495
account. For optimal dosing of CYC in patients with renal
insufficiency, the severity of renal impairment and the use and
timing of hemodialysis have to be considered.
Intravenous pulse therapy with cyclophosphamide
(CYC), an alkylating agent with cytotoxic and immuno-
suppressive properties, is an established treatment for
systemic lupus erythematosus and has also been used suc-
cessfully in Wegener’s granulomatosis, microscopic poly-
angiitis and other autoimmune diseases [1, 2]. Renal in-
volvement is frequent in these diseases and therefore
patients often present with renal insufficiency or even
terminal renal failure. CYC is a prodrug that undergoes
extensive metabolism to form active (alkylating) and
inactive products [3–6]. Both the metabolites and a frac-
tion (up to 25%) [3, 5] of unchanged parent compound
are ultimately eliminated from the body by the kidneys
[7]. Despite this fact and the frequent use of CYC in the
presence of impaired renal function, data regarding the
clinical pharmacokinetics of CYC in patients with renal
insufficiency are limited and controversial. Some studies
report no changes in the pharmacokinetics and toxicity
profile of CYC in the presence of reduced renal function,
leading the authors to suggest that dosage adjustment is
not recommended [3, 4, 8]. In contrast, other investiga-
tors found a decreased clearance of both CYC [9] and its
alkylating metabolites [7, 10] in association with an en-
hanced toxicity [7]. Furthermore, few data exist regard-
ing the impact of hemodialysis on the pharmacokinetics
of CYC, and the optimal timing of dialysis in uremic pa-
tients receiving intravenous CYC therapy still remains
controversial [11–13]. We therefore investigated the im-
pact of renal insufficiency and hemodialysis on the phar-
macokinetics of CYC, in order to provide additional data
as a rational base for the establishment of treatment guide-
lines for CYC in patients with impaired renal function.
1496 Haubitz et al: Cyclophosphamide in renal insufficiency
Table 1. Patient characteristics
Controls
Characteristics CCr ⱖ80 mL/min
N 12
CCr mL/min
Mean ⫾ SD 122 ⫾ 35
Range 80–196
Hemodialysis No
Gender females/males 12/0
Age years
Mean ⫾ SD 43 ⫾ 8
Weight kg
Mean ⫾ SD 63 ⫾ 11
Daily prednisolone dose mg
Mean ⫾ SD — 16 ⫾ 7
METHODS
Patients
Fifteen patients with autoimmune diseases and im-
paired renal function [creatinine clearance (CCr) ⬍50 mL/
min] who were scheduled for a pulse therapy with CYC
were included in this study. The underlying diseases were
histologically proven ANCA-associated vasculitis [Weg-
ener’s granulomatosis (WG), N ⫽ 5; microscopic polyan-
giitis (MPA), N ⫽ 5], systemic lupus erythematosus
(SLE) with lupus nephritis (N ⫽ 3), ankylosing spondy-
larthritis with amyloidosis (N ⫽ 1) and rapidly progres-
sive IgA nephropathy with multiple crescents in the kid-
ney biopsy (N ⫽ 1). The diagnosis MPA or WG was made
according to the definition of the International Consen-
sus Conference at Chapel Hill and criteria described
previously [2]. SLE was diagnosed according to the re-
vised criteria of the American College of Rheumatology
[14]. Patients had normal liver function as assessed by
standard laboratory parameters. During the study course,
all patients were on maintenance treatment with predni-
solone (Table 1) in addition to individual co-medication
(most frequently loop diuretics, ACE inhibitors, calcium
channel antagonists, antacids and vitamin D). Further
medication on the day of CYC administration included
ondansetron and mesna. The study was approved a priori
by the local ethics committee and written informed con-
sent was obtained from each patient.
Patient characteristics are summarized in Table 1. Pa-
tients were divided into three groups according to renal
function, as assessed by the measurement of creatinine
clearance following a 24-hour urine collection. In group A
(N ⫽ 6), CCr was between 25 and 50 mL/min; in group B
(N ⫽ 5) the CCr values were between 10 and 24 mL/min;
and group C (N ⫽ 6) had CCr levels below 10 mL/min plus
hemodialysis treatment. Group C included two patients
who were re-investigated with recovered renal function
in groups A and B, respectively. Twelve previously re-
ported patients with normal kidney function receiving
Group A Group B Group C
CCr 25–50 mL/min CCr 10–24 mL/min CCr ⬍10 mL/min
6 5 6
33 ⫾ 9 20 ⫾ 4 4⫾4
25–49 14–24 0–9
No No Yes
4/2 2/3 2/4
52 ⫾ 20 61 ⫾ 18 54 ⫾ 20
79 ⫾ 15 69 ⫾ 6 66 ⫾ 8
25 ⫾ 19 34 ⫾ 26
similar doses of CYC (as a one hour infusion) for the
treatment of breast cancer served as the reference [5].
CYC administration and sample collection
Pulse therapy with CYC consisted in monthly infusions
with 500 to 1000 mg/m2 CYC (Endoxan威; Asta Medica,
Frankfurt, Germany), administered as a one-hour infu-
sion in physiological sodium chloride. The individual
dose was determined independently of the study, ac-
cording to the clinical judgment of the treating physician.
To avoid any time conflict between the organizational
requirements of the present pharmacokinetic investiga-
tion and the clinical handling of the patients, the patients
were enrolled in the study only during their second
course of CYC pulse therapy. In addition, two patients
were re-investigated at a later time-point (see last sec-
tion). Although CYC is known to induce its own metabo-
lism (most likely by induction of the cytochrome P450
enzymes involved in its biotransformation [15, 16]), a
persistence of the effects of induction generated by one
CYC infusion over the dose-interval of four weeks ap-
pears extremely unlikely. For example, it has been shown
for cytochrome P4503A4 that the half-life of decrease
in enzyme activity after discontinuation of the enzyme
inducing agent rifampin averaged 1.5 to 2.1 days [17]. In
addition, pharmacokinetics of CYC in patients during
four consecutive treatment cycles showed no trend for
an enhanced CYC elimination with increasing number
of courses [5].
Blood without anticoagulant was drawn before and
1, 2, 4, 8, 14 and 24 hours after the start of the CYC-
infusion, centrifuged immediately and separated serum
stored at ⫺70⬚C until analysis. In patients with end-stage
renal failure (group C), a three-hour bicarbonate dialysis
using a polysulfone membrane (F6HPS 1.3 m2 surface;
Fresenius, Bad Homburg, Germany) was initiated 7 hours
after the end of the CYC infusion. Dialysate flow was
500 mL/min and a blood flow of 200 mL/min was chosen.
Blood samples and dialysate samples were drawn after
 Haubitz et al: Cyclophosphamide in renal insufficiency
0, 1, 2 and 3 hours of dialysis, respectively, and stored
at ⫺70⬚C until analysis.
Measurement of CYC
Concentrations of cyclophosphamide in serum, urine
and dialysate were determined by high-pressure liquid
chromatography (HPLC) as described previously [5],
with the following modifications. Samples were spiked
with the internal standard ifosfamide and extracted using
200 mg Bond Elut C8 solid-phase extraction columns
(Baker, Gro␤-Gerau, Germany). After conditioning and
sample load the columns were washed with 4 mL of
water, then dried by applying vacuum and eluted with
1 mL of methanol. The eluate was evaporated to dryness
under a stream of nitrogen, redissolved in 1 mL of water
and extracted with 4 mL of ethyl acetate before centrifu-
gation, evaporation and redissolving of the organic phase
as previously described [5]. The column was maintained
at 37⬚C and consisted of a Prontosil 120 C18 AQ column
(150 ⫻ 3 mm ID, 3 ␮m particle size) with a Hypersil
C18 precolumn.
Pharmacokinetic analysis
The area-under-the-curve (AUC, calculated from 0 to
infinity), systemic clearance (CL), renal clearance (Cren),
volume of distribution (Vss), elimination half-life (t1/2),
and amount of CYC excreted unchanged in urine (Ae),
were calculated by standard procedures as previously
described [5]. Total amount of CYC cleared by the three-
hour dialysis was calculated by ⌺hour 1-3 [CYC in dialysate
(ng/mL) · dialysate volume (mL)]. Coefficients of varia-
tion were calculated as the percentage of standard devia-
tion to mean value.
Statistical analysis
All data are presented as mean ⫾ standard deviation
(SD). Multiple comparisons were analyzed by ANOVA
with subsequent Tukey-Kramer tests or, if required, by
the Kruskal Wallis test (nonparametric ANOVA) with
subsequent Dunn’s test. The correlation of CCr with dif-
ferent pharmacokinetic parameters of CYC (dose cor-
rected AUC, CL, Cren) was tested by use of the Spearman
Rank correlation. A value of P ⱕ 0.05 was required for
statistical significance.
RESULTS
Mean administered CYC dose was 1.4 ⫾ 0.1 g
(group A), 1.1 ⫾ 0.2 g (group B), 1.2 ⫾ 0.4 g (group C),
and 0.83 ⫾ 0.05 g (controls). Even when taking into
consideration the differences in administered doses, the
course of the serum-concentration time curves of CYC
1497
Fig. 1. Serum concentration-time curves of cyclophosphamide (CYC)
following a one-hour infusion. Symbols are: (䉱) controls (CCr ⬎80
mL/min; CYC dose 0.8 ⫾ 0.1 g); (䊉) group A (CCr 25 to 50 mL/min;
CYC dose 1.4 ⫾ 0.1 g); (䊐) group B (CCr 10 to 25 mL/min; CYC dose
1.1 ⫾ 0.2 g); (䊊) group C (CCr ⬍10 mL/min, treated with a 3-hour
hemodialysis during the study period, CYC dose: 1.2 ⫾ 0.4g). Data are
mean ⫾ SD.
(Fig. 1) suggests that serum levels of CYC gradually
increase as renal function decreases. Moreover, it shows
that a rapid fall of CYC serum concentrations occurs
during dialysis, thereby indicating effective elimination
of the drug from the systemic circulation. In fact, a total
amount of 317 ⫾ 43 mg CYC (corresponding to 22 ⫾ 3%
of administered dose) were recovered in the dialysate
following a three-hour dialysis in the patients with end-
stage renal disease (group C). In line with these findings,
systemic drug exposure was increased in the presence of
renal insufficiency, the dose corrected AUC being 42%
(NS) and 77% (P ⬍ 0.01) higher in groups A and B, re-
spectively, than in controls (Fig. 2). The difference was
less pronounced in the patients with terminal renal fail-
ure who received a three hour dialysis during the study
period (⫹23%, NS). Systemic clearance of CYC was sig-
nificantly reduced in relation to renal impairment (⫺28%,
P ⬍ 0.01 and ⫺41%, P ⬍ 0.001, for groups A and B vs.
controls, respectively), and only moderately lower in the
HD-treated group C (⫺19%, NS; Fig. 2). Body weight
correction of systemic clearance generated similar results
(data not shown). Renal clearance of CYC was almost
negligible in patients with reduced renal function and
reduced by 76 to 86% when compared to controls (14.9 ⫾
3.7 vs. 3.4 ⫾ 1.6, 2.4 ⫾ 1.2 and 2.1 ⫾ 1.1 mL/min; for
controls vs. group A, group B and group C, respectively,
P ⬍ 0.001). Accordingly, the percentage of administered
dose excreted unchanged into urine was significantly re-
duced (Fig. 2). To further substantiate a possible rela-
tionship between renal function and pharmacokinetics
of CYC, we found a significant correlation between CCr
and the renal and systemic clearance of CYC, respec-
1498 Haubitz et al: Cyclophosphamide in renal insufficiency
tively (Fig. 3 A, B). Moreover, there was a significant
inverse correlation between CCr and dose corrected AUC
of CYC (Fig. 3C).
Compared to controls, terminal elimination half-life of
CYC was prolonged in the presence of renal insufficiency
(Fig. 2). Finally, the volume of distribution of CYC was
in the same range in the controls and the dialysis-treated
patients, but significantly lower in the patients with renal
insufficiency who were not under hemodialysis (controls,
0.49 ⫾ 0.1; group A, 0.36 ⫾ 0.1; group B, 0.36 ⫾ 0.1;
group C, 0.49 ⫾ 0.1 L/kg, P ⬍ 0.05 for group A and
group B vs. controls or group C, respectively).
DISCUSSION
Our results clearly indicate that pharmacokinetics of
CYC are altered in patients with renal insufficiency.
Compared to patients with normal renal function, we
found an increased systemic drug exposure associated
with a reduced systemic clearance and a prolonged elimi-
nation half-life, the magnitude of the kinetic alterations
being related to the degree of renal insufficiency. Of
note, the difference in mean administered CYC doses
between our patient groups is unlikely to affect pharma-
Fig. 2. Pharmacokinetic parameters of CYC
in patients with normal renal function (con-
trols, N ⫽ 12), patients with moderate renal
insufficiency (group A, CCr 25 to 50 mL/min,
N ⫽ 6), severe renal insufficiency (group B,
CCr 10 to 25 mL/min: N ⫽ 5) and hemodialysis-
dependent end-stage renal disease (group C,
CCr ⬍10 mL/min and treated with a 3-hour
hemodialysis during the study period, N ⫽ 6).
Data are mean ⫾ SD. *P ⬍ 0.05, †P ⬍ 0.01
and ‡P ⬍ 0.001 vs. controls; 䊊P ⬍ 0.05 vs.
patient group A.
cokinetic results, as no effect of dose on the main phar-
macokinetic parameters of unchanged CYC was ob-
served over the standard dose ranges used clinically [4, 7].
Moreover, no significant age- and gender-related differ-
ences in pharmacokinetics of CYC have been docu-
mented in adults so far [3, 4, 7]. Modification of CYC
metabolism by prednisolone has been reported in the
literature, although with few studies and contradictory
results [7, 18–21]. In six patients, maintenance treatment
of 12 to 14 days with oral doses of 50 mg prednisolone
reduced the terminal elimination half-life (mean ⫺19%)
and increased the biotransformation rate of CYC [18].
Assuming CYC metabolism is in fact induced by predni-
solone, the steroid co-medication (which was given to the
patients with renal insufficiency but not to the “control”
subjects) may even lead to an underestimation of the re-
duction of CYC elimination in our patients with reduced
renal function. Ondansetron, which was given as anti-
emetic, has been reported to decrease the AUC of cyclo-
phosphamide by yet not completely identified mecha-
nisms [22, 23]. However, as ondansetron was given in
similar doses to all the patients of the study (including
the 12 patients with normal renal function who served
as controls), any effect of ondansetron on CYC pharma-
 Haubitz et al: Cyclophosphamide in renal insufficiency
Fig. 3. Correlation between individual creatinine clearance (CCr) val-
ues and renal clearance (A), systemic clearance (B) and dose corrected
area-under-the-curve (AUC; C) of CYC (0.5 to 1.0 g/m2 as a 1-hour
infusion) in 12 patients with normal renal function (CCr ⬎80 mL/min),
6 patients with moderate renal insufficiency (CCr 25 to 50 mL/min), 5
patients with severe renal insufficiency (CCr 10 to 25 mL/min) and (only
in panel A) 6 patients with end-stage renal disease receiving a 3-hour
hemodialysis during the study period (CCr 0 to 10 mL/min).
cokinetics would be systematic and therefore would not
bias the reported differences in CYC pharmacokinetics
between the patient groups.
Our data are in agreement with the data of Juma, Rog-
ers and Trounce, who reported a decrease in clearance
(⫺17%) and an increase in half-life (⫹24%) of CYC in
six patients with a CCr of 18 to 51 mL/min in comparison
to eight matched controls with normal renal function [8].
Both the significant reduction in renal clearance of CYC
found in our study and the fact that the biotransforma-
tion rate has been shown to be unaffected in patients
with renal impairment [10] suggest a decreased renal
excretion of intact parent compound to be a relevant
factor responsible for the decreased systemic clearance
1499
of CYC in patients with renal insufficiency. In addition,
the smaller volume of distribution found in patients with
renal insufficiency represents a further factor contribut-
ing to an increased plasma availability of CYC.
As indicated by the results of patient group C, the
hemodialysis partly compensated the pharmacokinetic
changes induced by the reduced kidney function. Based
on the serum concentration levels before hemodialysis,
the almost completely reduced renal elimination and the
prolonged half-life of CYC, one would have expected
the highest systemic drug exposure in the patients with
terminal renal failure (group C). However, the increase
in dose corrected AUC and decrease in clearance were
less pronounced than in those patients with residual renal
function (groups A and B). This is explained by the
fact that up to 25% of administered CYC dose were
recovered in the dialysate and thus removed from the
body during the three-hour dialysis, with a consequent
reduction in overall drug exposure. If one considers that
the time-lack between the end of the CYC infusion and
the start of the hemodialysis (that is, 7 hours) equals one
half-life of CYC (which means that only about half of
the administered CYC dose can be assumed to still have
been in the patient’s body at the time of hemodialysis),
the amount of CYC removed by the dialyzer corresponds
to approximately 50% of currently present drug. Similar
to our data, Wang et al reported a drug removal of 37%
during a four-hour dialysis started directly at the end of
CYC administration in four patients with chronic renal
failure, and estimated an average recovery of 74% for
a six-hour dialysis period [11]. The fact that CYC is
dialyzable is not unexpected as it is a small un-ionized
molecule with low protein binding and a distribution
volume that equals total body water.
The establishment of a dose-effect relationship for
CYC is not only hampered by the general multifactorial
problem of inter-patient variability in pharmacokinetics
and pharmacodynamics, but also by the fact that the com-
plex metabolism and precise mechanism of action of the
drug itself are not yet completely understood [3, 4, 6, 7].
Thus, few data are available relating plasma levels of
CYC to therapeutic efficacy or toxicity in humans and,
similarly, studies correlating the clinical effects of impaired
renal function and CYC dosage are sparse. Whereas some
report no association between renal insufficiency and
toxicity of CYC [reviewed in 4], Bagley, Bostick and De
Vita observed appreciable hematological toxicity and
prolonged retention of alkylating materials in one pa-
tient with renal failure (CCr 18 mL/min) [7], and a recent
case report describes unexpected severe toxicity (includ-
ing myocarditis) in a myeloma patient with renal failure
following treatment with CYC [24]. From clinical experi-
ence, the use of standard CYC doses in patients with
renal insufficiency is associated with increased toxicity,
mainly leukopenia, anemia and infection. However, it is
1500 Haubitz et al: Cyclophosphamide in renal insufficiency
not clear whether this is due to an increased drug effect
or to a reduced bone marrow capacity caused by the
uremia and the underlying disease. Our results indicate
that the use of standard dosage in patients with severely
impaired renal function will result in an increased sys-
temic drug exposure. Based on Figure 3C, for a given dose
of CYC one would predict a 20 to 30% higher AUC in
patients with a CCr of ⱕ30 mL/min as compared to pa-
tients with a CCr in the range of 80 to 120 mL/min. Al-
though the clinical effects of CYC are mediated by me-
tabolites, the reduced renal loss of intact drug represents
a net increase in available parent compound to be poten-
tially bioactivated. Our assumption is supported by the
study of Chen et al, who found that a higher CYC expo-
sure is associated with a higher exposure toward its bio-
activated metabolites, 4-hydroxycyclophosphamide/aldo-
phosphamide, and which could demonstrate in a computer
simulation that a 90% reduction of the renal CL of CYC
may be associated with a 30% increase in the AUC of
4-hydroxycyclophosphamide/aldophosphamide [25]. De-
spite its clinical efficacy, CYC treatment of autoimmune
disorders remains a therapy that is accompanied by seri-
ous side effects, and current trials are still aimed at de-
termining the most effective and least toxic regimen. The
fact that, in terms of overall toxicity, a reduction of the
total dose required is thought to be the advantage of
pulse therapy when compared to continuous oral regi-
men [2, 26] emphasizes the critical role of CYC dosage.
Based on our results, a dose reduction of 20 to 30%
(depending on the degree of renal insufficiency) is sug-
gested, which would still ensure adequate systemic expo-
sure of parent compound by normalizing the AUC to-
ward the ranges as present in patients with normal kidney
function but potentially prevent additional therapy-
related toxicity.
In patients on chronic dialysis treatment CYC elimina-
tion by the dialysis procedure has to be taken into ac-
count. Given the high dialysis clearance of CYC, the
suggestion of Wagner et al to start dialysis as early as
two hours after CYC [13] and the recommendation of
Milsted and Jarman that no interruption of hemodialysis
is required during treatment with CYC [12] implicate
the risk of inadequate low immunosuppressive effect.
As the prevention of chronic organ damage depends on
an early effective treatment [27], this should be avoided.
Based on our results, dialysis should not be initiated
earlier than 12 hours after CYC infusion (most easily
the day after CYC administration), which would prevent
drug removal in the early distribution phase but would
still correct for the prolonged terminal elimination phase.
For decades, it has been widely accepted that impaired
renal function would not alter the pharmacokinetic be-
havior of CYC because its clearance is primarily via
nonrenal mechanisms. The present data clearly demon-
strate the impact of renal insufficiency and hemodialysis
on the disposition of CYC and thus emphasize the impor-
tance of individualized dosage in this group of patients.
For optimal dosing of CYC in patients with reduced
kidney function, the degree of renal impairment and the
use and timing of hemodialysis should be considered.
ACKNOWLEDGMENTS
This study was supported by the Robert Bosch Foundation, Stutt-
gart, Germany. The authors thank the clinical fellows, clinical center
nursing staff and the Zentralapotheke for their help during the study,
and Martina Flechsig, Monika Seiler, Anja Ziegler and Susanne John-
son for excellent technical assistance.
Reprint requests to Dr. Marion Haubitz, M.D., Department of Ne-
phrology, Medical School Hannover, 30623 Hannover, Germany.
E-mail: Haubitz.Marion@Mh-Hannover.de
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