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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4436-4440
The Impact of Obesity and Disease on Busulfan Oral Clearance in Adults
By
John P. Gibbs,
Ted Gooley,
Bruce Corneau,
Georgia Murray,
Patricia Stewart,
Frederick R. Appelbaum, and
John T. Slattery
From Fred Hutchinson Cancer Research Center, Seattle WA; and
Department of Pharmaceutics, University of Washington, Seattle, WA.
 |
ABSTRACT |
The apparent oral clearance (CL/F, mL/min) of busulfan was measured
in 279 adolescent and adult patients. Significant (P < .05) determinants of CL/F by linear regression were: actual
body weight (BW; r2 = 0.300), body surface area (BSA;
r2 = 0.277), adjusted ideal body weight (AIBW;
r2 = 0.265), and ideal body weight (IBW; r2
= 0.173); whereas body mass index (BMI), height, age, gender, and
disease were less important predictors. CL/F (mL/min) for normal weight
patients (BMI, 18 to 27 kg/m2) was 16.2% lower (P < .001) than for obese patients (BMI, 27 to 35 kg/m2).
Thus, expressing CL/F relative to BW did not eliminate statistically significant differences between normal and obese patients. However, busulfan CL/F expressed relative to BSA (110 ± 24 v 110 ± 24 mL/min/m2, P = 1.0) or AIBW (3.04 ± 0.65 v 3.19 ± 0.67 mL/min/kg, P = .597) were
similar in normal and obese patients. Non-Hodgkin's lymphoma patients
(n = 10) had approximately 32% lower mean busulfan CL/F expressed
relative to BW, BSA, or AIBW compared with patients with chronic
myelogenous leukemia (n = 73). Routine dosing on the basis of BSA or
AIBW in adults and adolescents does not require a specific
accommodation for the obese. However, dosing based on BSA may be
improved by considering CL/F differences in certain diseases. Adjusting
dose for body size or disease does not diminish interpatient
variability sufficiently to obviate plasma level monitoring in many indications.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
BUSULFAN IS A BIFUNCTIONAL alkylating
agent commonly used in preparative regimens before hematopoietic stem
cell transplantation for treatment of various malignancies and
inherited disorders. In hematopoietic stem cell transplantation,
outcome at a fixed mg/kg dose has been related to area under the plasma
concentration-time curve (AUC) and average steady-state concentration
(CSS). Excessively high busulfan AUC or CSS is
associated with an increase in hepatic veno-occlusive disease, low
levels are associated with a higher relapse rate in patients with
chronic myelogenous leukemia (CML), and lower levels are associated
with graft rejection in allogeneic transplantation.1-4 Both
AUC and CSS are inversely proportional to apparent oral
clearance (CL/F) and are directly proportional to dose.
In many instances, busulfan is administered orally on a fixed mg/kg
basis without dosage adjustment to achieve target busulfan plasma
concentrations. The practice of normalizing doses to body size
diminishes variability in clearance among patients.5
However, the problem faced in dosing obese patients is choosing the
appropriate measure of body size with which to calculate dose, because
actual body weight is intuitively questioned. Previously, we found that among the commonly used body size parameters (ie, actual body weight
[BW], ideal body weight [IBW], adjusted body weight [AIBW], and
body surface area [BSA]), expressing busulfan CL/F relative to BSA
produced the lowest coefficient of variation in 42 children and
adults,3 although AIBW performed nearly as well. The body size measure that produces the minimum variability in CL/F is the most
appropriate for the calculation of dose because it will minimize
variability in the resultant AUC or CSS in comparison to
alternative measures of body size.
Disease has also been linked to alterations in busulfan
pharmacokinetics. Previous studies have shown that the disposition of
busulfan is altered in children with inherited disorders. Children with
lysosomal storage diseases have been reported to have longer elimination half-lifes, and a trend towards higher CL/F compared with
children with immune deficiencies, acute leukemias, and malignant lymphohistiocytosis.6 Children with inherited genetic
disorders have been reported to have enhanced elimination half-lifes
after the first dose of busulfan and elevated busulfan CL/F compared with children with leukemias,7 although patient numbers
were small.
The only known pathway for the elimination of busulfan involves
glutathione (GSH) conjugation to form
 -glutamyl- -(S-tetrahydrothiophenium ion) alanyl-glycine
(THT+). Busulfan is uncommon in this respect, because there
are few other drugs that are primarily eliminated by GSH conjugation. We have found that human cytosolic glutahione S-transferase
(GST) catalyzes THT+ formation,8 and that
GSTA1-1, the major liver GST, is the predominant GST isoform in
busulfan conjugation.9 Less than 2% of an oral busulfan
dose is excreted unchanged.10 The effect of obesity on
GSTA1-1 activity is unstudied.
The purpose of this report is to compare busulfan CL/F in obese and
normal patients treated for various diseases to provide a
pharmacokinetic rationale for the appropriate dosing of busulfan, and
to gain insight on the activity of GSTA1-1 in obesity and disease. We
used a base of 279 adult and adolescent patients undergoing hematopoietic stem cell transplantation at the Fred Hutchinson Cancer
Research Center (Seattle, WA) between January 1992 and December 1996, in whom busulfan CL/F had been measured on at least two occasions
during conditioning for hematopoietic stem cell transplantation.
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MATERIALS AND METHODS |
Patients.
Records collected as part of routine clinical busulfan monitoring
between January 1992 and December 1996 at the Fred Hutchinson Cancer
Research Center were examined retrospectively. Inclusion required that
the patients were in treatment protocols that stipulated busulfan
monitoring. These patients represent about 32% of all patients treated
with a busulfan-based conditioning regimen during that time period. The
patients provided informed consent for the pharmacokinetic analysis.
All patients with complete information (consisting of age, dose,
disease, height, weight, dose five CL/F, and dose nine CL/F) were
included in the analysis, and individuals less than 12-years old (due
to age-dependence in busulfan CL/F3,11) or greater than
60-years old were excluded. The final database contained 279 patients
who received 0.44 to 1.8 mg/kg oral busulfan tablets every 6 hours for
4 days as part of their transplant preparative regimen. No other
cytotoxic agents or irradiation were administered immediately before or
concomitantly with busulfan. Patients received phenytoin for seizure
prophylaxis. The diseases treated included acute myelogenous leukemia
(AML; n = 60), breast cancer (BrCa; n = 55), (CML; n = 73),
myelodysplastic syndrome (n = 49), multiple myeloma (MM; n = 25),
non-Hodgkin's lymphoma (NHL; n = 10), and ovarian cancer (n = 7).
Determination of CL/F.
Blood samples were collected just before and 60, 120, 180, 240, and 360 minutes after the administration of busulfan. Plasma busulfan
concentrations were determined by gas chromatography with mass
selective detection, and mean CL/F was calculated for the 5th and 9th
doses of busulfan as previously described.3 Body size
estimates were calculated using the following equations in which height
is measured in cm and weight in kg.
Patients were classified by BMI: underweight, BMI < 18 kg/m2; normal, BMI 18 to 26.9 kg/m2; obese, BMI
27 to 35 kg/m2, and severely obese, BMI > 35 kg/m2. BMI and the percentage of BW relative to IBW are
correlated (BMI = 0.2 (%IBW) + 2.10, r2 = 0.907), such
that a BMI of 27 corresponds to 125% BW/IBW.
Statistical analysis.
All statistical comparisons were performed using SPSS version 7.5 (SPSS
Inc, Chicago, IL). In univariable linear regression analysis, the relationship between CL/F (mL/min) and each of the following individual patient variables was assessed: age, AIBW, BMI,
BSA, height, IBW, gender, disease, and BW. One-way analysis of variance
(ANOVA) was used to compare differences in body size-normalized CL/F
among different disease categories with the Bonferroni correction for
multiple comparisons. The Levene statistic was used to test for
homogeneity of variance.
| |
RESULTS |
In univariable linear regression analysis, the regression coefficients
for absolute busulfan CL/F and each of the following variables were: BW
(r2 = 0.300), BSA (r2 = 0.277), AIBW
(r2 = 0.265), IBW (r2 = 0.173), height
(r2 = 0.164), BMI (r2 = 0.176), and age
(r2 = 0.019). Figure 1 shows
the relationship between absolute busulfan CL/F and BW, BSA, AIBW, and
IBW. All correlations were statistically significant (P < .001; except for age, P = .022). This analysis suggests that
BW, BSA, and AIBW are comparable single predictors of CL/F.
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| Fig 1.
The relationship between busulfan CL/F (mL/min) and BW,
BSA, IBW, and AIBW in underweight (BMI < 18 kg/m2; n = 7), normal (BMI 18 to 26.9 kg/m2; n = 173), obese (BMI
= 27 to 35 kg/m2; n = 89), and severely obese (BMI > 35 kg/m2; n = 10) patients.
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Busulfan CL/F is listed in Table 1 for
patients in four BMI categories: underweight, normal, obese, and
severely obese. The ratio of BW:IBW for each respective BMI category
was: 78.4% ± 7.4% (range, 65.6% to 88.1%), underweight; 106% ± 12% (range, 76.4% to 138%), normal; 136% ± 13% (range,
117% to 166%), obese; and 177% ± 23% (range, 151% to 215%),
severely obese. Statistically significant differences in absolute
(mL/min) CL/F between genders were noted within normal and obese
categories. (We did not test for gender differences in the underweight
and severely obese patients due to the small sample size of these BMI
categories (n = 7 and n = 10, respectively.) Males had a higher
absolute (mL/min) CL/F than females in both normal and obese patients.
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Table 1.
Busulfan CL/F* in Underweight (BMI <18
kg/m2), Normal (BMI = 18 to 26.9 kg/m2),
Obese (BMI = 27 to 35 kg/m2), and Severely Obese
Patients (BMI >35 kg/m2)
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We compared the mean CL/F among underweight, normal, obese, and
severely obese patients using one-way ANOVA
(Table 2). Absolute (mL/min) CL/F was
elevated in obese (17%) and severely obese (32%) patients compared
with normal patients, P < .05, but there was no statistical
difference in CL/F for normal and underweight patients. CL/F relative
to BW (mL/min/kg) was 12% and 21% lower in obese and severely obese
patients compared with normal patients, respectively, and 32% higher
in underweight patients compared with normal patients. There was not a
statistically significant difference in CL/F relative to BSA
(mL/min/m2) or AIBW (mL/min/kg AIBW) among underweight,
normal, obese, and severely obese patients. We compared busulfan CL/F
as a function of age by decade (Table 3).
There was no age-dependence in busulfan CL/F when expressed relative to
BSA or AIBW.
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Table 2.
Statistical Comparisons of Table 1 Mean Busulfan CL/F
Among Underweight, Normal, Obese, and Severely Obese Patients
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Busulfan CL/F was compared among disease categories after expressing
busulfan CL/F relative to BW, AIBW, and BSA
(Table 4). There was a statistical
difference when comparing the mean CL/F expressed relative to BW in
patients with NHL to those with AML (2.15 ± 0.22 v 2.82 ± 0.66 mL/min/kg, P < .045, respectively), and NHL
v CML (2.15 ± 0.22 v 2.92 ± 0.70 mL/min/kg,
P < .007, respectively). Significant differences in mean
busulfan CL/F expressed relative to BSA were found in patients with NHL
in comparison to those with CML (87.9 ± 12.3 v 116 ± 25 mL/min/m2, P < .006, respectively). The mean CL/F
expressed relative to AIBW was statistically significantly different in
patients with NHL compared with those with BrCa (2.41 ± 0.42 v 3.15 ± 0.62 mL/min/kg, P < .017, respectively),
NHL v CML (2.41 ± 0.42 v 3.20 ± 0.70 mL/min/kg,
P < .006, respectively), and NHL v MM (2.41 ± 0.42 v 3.24 ± 0.61 mL/min/kg, P < .012, respectively).
We sought an effect of elevations in liver function tests (ie, alkaline
phosphatase, alanine aminotransferase, and aspartate aminotransferase)
and kidney function tests (ie, blood urea nitrogen and creatinine) on
busulfan CL/F expressed relative to BSA. The normal range for each test
was: alkaline phosphatase, 50 to 120 U/L; alanine aminotransferase, 10 to 35 U/L; aspartate aminotransferase, 20 to 48 U/L; blood urea
nitrogen, 5 to 20 mg/dL; and creatinine, 0.1 to 1.1 mg/dL. We found
that elevations in liver and kidney function tests were not significant
predictors of changes in CL/F relative to BSA (P > .14).
Also, 15 patients included in this analysis were undergoing a second
transplant (at least 3 months after the first transplant). There was no
difference in the mean CL/F relative to BSA for patients undergoing
first versus second transplant (109 ± 23 v 107 ± 22 mL/min/m2, P = .732, respectively).
| |
DISCUSSION |
The major finding was that although CL/F varies among BMI classes when
expressed relative to BW, there are no differences in busulfan CL/F
among BMI classes when CL/F is expressed relative to AIBW or BSA
(Tables 1 and 2). Patients with NHL (n = 10) had lower
busulfan CL/F expressed relative to BW, BSA, or AIBW compared with
patients with CML (Table 4).
The current clinical practice at most transplant centers is to dose
busulfan relative to body weight or adjusted ideal body weight,
although there is a dilemma about what to do in the obese. BSA or
AIBW-adjusted dosing will eliminate differences in busulfan CL/F among
normal and obese patients, but it does not eliminate disease-specific
differences. There were no differences in busulfan CL/F expressed
relative to BSA or AIBW in underweight patients compared with obese and
severely obese patients. Therefore, these measures of body size are
appropriate for calculating dose in any adult. The data suggest that it
may be prudent to lower the dose/m2 or dose/kg AIBW in NHL
patients if it were desired to produce equivalent mean AUC or
CSS in all patients.
The relationship between busulfan CSS and a variety of
outcomes has been examined. Busulfan CSS was related to
regimen-related toxicity (RRT) and graft rejection in 42 patients with
a variety of diseases undergoing hematopoietic stem cell
transplantation.3 Severe-grade 3-4 RRT was only observed in
patients with CSS > 900 ng/mL. The incidence of graft
rejection for those receiving HLA partially matched related or
unrelated donor grafts with a busulfan CSS < 600 ng/mL
was 7 in 9, whereas graft rejection in patients with
CSS > 600 ng/mL was 1 in 7. Based on these
findings, the therapeutic window for busulfan is CSS of 600 to 900 ng/mL (which corresponds to mean AUC of 900 to 1,350 µmol/L × minute) over 16 doses for these patients.3 More
recent findings suggest that tolerance to busulfan may vary by disease.
CML patients tolerate busulfan CSS > 900 ng/mL without
severe-grade 3-4 RRT. 4 In addition, the incidence of
relapse was significantly higher in CML patients with busulfan
CSS levels below the median for the entire group of 45 patients (917 ng/mL).
Interpatient variability in busulfan CL/F is large and is an important
determinant of transplantation outcome. In the studies just cited (in
which patients received a constant mg/kg dose), inappropriate busulfan
AUC was the single most important determinant of toxicity, rejection,
or relapse. The coefficients of variation for busulfan CL/F expressed
relative to AIBW and BSA when including all patients in this study were
both 21.3%. Thus, given the frequency with which busulfan AUC will
exceed thresholds associated with undesired outcomes even when dose is
adjusted for AIBW or BSA, busulfan level monitoring is still required
in certain situations.
As mentioned previously, busulfan is eliminated by GSH conjugation
catalyzed by GST. The results of this study suggest that total GSTA1-1
activity is most closely related to BSA or AIBW. In general, absolute
(mL/min) clearances of xenobiotics (ie, caffeine, phenytoin,
desmethyl-diazepam, carbamazepine, midazolam, and antipyrine) eliminated primarily by hepatic P450 oxidative metabolism (phase-I enzymes) are similar in obese and lean subjects,12-17
whereas absolute clearances of drugs eliminated primarily by phase-II
enzymes (ie, phenol sulfotransferase, glucuronyl transferase) are
higher in obese subjects compared with lean controls.18-21
The findings with busulfan are similar to those with other drugs
eliminated by phase-II enzymes (GST is a phase-II enzyme).
Interestingly, NHL patients had lower busulfan CL/F when expressed
relative to BW, BSA, or AIBW compared with patients with CML, whose
CL/F relative to BW, BSA, and AIBW was 4.5%, 6.0%, and 3.8% higher
than the mean of all patients, respectively. The reason for a lower
CL/F in NHL is not clear, but it does not seem to be prior
chemotherapy. For example, 85% of CML patients received hydrea, and
34% alpha-interferon. For AML, 80% of patients received cytosine
arabinoside. In contrast, NHL patients received a range of therapies.
NHL patients that did not receive prior chemotherapy (3 in 10) had a
similar CL/F compared with those that did (5 in 10; 80.3 ± 7.0 v 88.8 ± 13.0 mL/min/m2, P = .28, respectively). Data on prior chemotherapy were not available for two patients.
After the standard 1 mg/kg (BW) busulfan dose, a patient with CL/F of
2.9 mL/min/kg (the mean value for patients with BMI between 18 and 27 kg/m2) will have a CSS of 960 ng/mL (which
corresponds to an AUC of 1,400 µmol/L × minute). NHL patients
administered a 1 mg/kg dose will have a CSS of 1,290 ng/mL
respectively, (which corresponds to AUC of 1,890 µmol/L × minute, respectively). Previous studies have identified the threshold
for severe toxicity to be CSS of 900 to 1,000 ng/mL (AUC of
1,350 to 1,500 µmol/L × minute).1-3 Thus, current
data suggest that the apparent reduction in busulfan CL/F in NHL
patients could result in enhanced toxicity after a fixed 1 mg/kg dose.
However, the small number (n = 10) of NHL patients included in this
analysis suggests that this issue should be investigated further.
In conclusion, absolute busulfan CL/F is elevated in obesity.
Expressing CL/F relative to AIBW or BSA eliminated mean differences in
CL/F among underweight, normal, obese, and severely obese patients. There appears to be a potentially important difference between NHL
patients and those with CML in busulfan CL/F expressed relative to BW,
BSA, or AIBW. Even when expressed relative to BSA or AIBW, interpatient
variability in busulfan CL/F expressed relative to any measure of body
size is large relative to the therapeutic window in certain
indications.3,4 The need for adjusting busulfan dose based
on AUC or CSS measured in the individual patient remains in
certain settings regardless of body size measure.
| |
FOOTNOTES |
Submitted April 28, 1998; accepted January 14, 1999.
Supported in part by National Institutes of Health Grant (CA 18029).
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.
Address correspondence to John T. Slattery, PhD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D2-100, Seattle, WA 98109-1024;
e-mail: jts{at}u.washington.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
