ONCOLOGY/IMMUNOTHERAPY
Pharmacokinetics of Intravenous Immunoglobulin (Gammagard) in Bone Marrow Transplant Patients Kenneth
MD,
H. Rand,
and
Katherine John
Gibbs,
Hartmut
Graham-Pole,
MD
Derendorf,
PhD,
pharmacokinetics of an intravenous immunoglobulin (WIG), Gammagard (Baxter Corp., Glendale, CA), were measured in 31 cytomegalovirus (CMV) antibody negative bone marrow transplant (BMT) patients as part of a multicenter efficacy trial of 2 weekly dose regimens. Since all patients lacked antibody to CMV and received only screened CMV negative blood products, the half-life of the exogenous CMV antibody could be measured with an ELISA assay. The CMV antibody titer was related to the immunoglobulin concentration using a standard curve. Compared with the 22-day halflife in normal subjects, the half-life in BMT patients was approximately 6 days for either the 250 mg/kg or 500 mg/kg dose regimen. The half-life did not change over the subsequent 3 weekly doses. Peak concentrations were 3.5 ± 1.4 and 2.6 ± 0.7 mg/mL of IVIG in week I as well as 5.5 ± 2.6 and 3.4 ± 1.2 mg/mL in week 3 after the 250 mg/kg and 500 mg/kg, respectively. Total body clearance of TVIG was 0.61 and 0.46 mL/kg/hr for the 500 mg/kg and 250 mg/kg, respectively. The
Healthcare
The use of intravenous immunoglobulin (IVIG) has become widespread among bone marrow transplant (BMT) patients for the prevention of cytomegalovirus (CMV) associated pneumonitis as well as other infectious complications.1-3 As measured by the rate of fall of CMV antibodies in CMV seronegative BMT patients receiving only CMV negative blood products, the half-life of IVIG in BMT patients appears to be markedly shortened. Although IVIG has the expected 22-day half-life in normal subjects, the halflife in BMT patients ranges from as low as 30 to 70 hours,4 to 3 to 6 days.5’6 In our previous study, we found the half-life of anti-CMV antibodies was 3.4 ± 2.0 days after the first dose of IVIG given 8 days before bone marrow infusion, and lengthened to 6.1 ± 5.1 days after the fifth weekly dose.6 As part of a multicenter efficacy trial to compare weekly doses of 250 versus 500 mg/kg IVIG, we stud-
From the Departments (Dr Rand), Pediatrics endorf),
University
Medical
Center,
Supported
of Pathology (Drs. Rand and Gibbs), (Dr. Graham-Pole), and Pharmaceutics of Florida
Gainesville,
by a grant
from
and
the
Department
Medicine
(Dr. Der-
of Veteran’s
Corporation,
the
pharmacokinetics
CMV seronegative that both dosing partment model kinetics.
of CMV
antibody
among
BMT patients. The data suggest levels of IVIG fit a linear one-comwith essentially identical pharmaco-
METHODS Patients Thirty-one patients undergoing allogeneic bone marrow transplantation at the Shands Hospital, University of Florida, between November 1987 and April 1990 who lacked antibodies to CMV before transplantation were studied. They ranged in age from 9 months to 46 years. There were 21 males and 10 females; 30 patients were white and I patient was black. The underlying diagnoses were as follows: chronic myelogenous leukemia 11, acute lymphocytic leukemia 8, acute myelocytic leukemia 6, lymphoma 2, severe thalassemia 1, myelofibrosis 1, myeloma 1, and aplastic anemia 1.
Affairs
Florida. Baxter-Healthcare
ied
Hyland
Divi-
Study
Design
sion. Address partment
for
reprints:
Kenneth
of Pathology,
J ClIn Pharmacol
H. Rand,
Box J-275,
1991;31:1151-1154
MD,
JHMHC,
University Gainesville,
of Florida, FL 32610.
De-
All
patients
commercial
were
tested
enzyme-linked
for antibody immunosorbent
to CMV
by assay
1151
a
RAND
(ELISA) before the administration of IVIG. Those patients who were seronegative for CMV received only CMV seronegative blood products. As part of a multicenter trial of gammagard for the prevention of CMV pneumonitis as well as other infections, patients were randomly assigned to receive either 250 mg/kg or 500 mg/kg IVIG weekly from day -8 before transplantation until day 112 post-transplantation. Sera were obtained before the first dose of IVIG, and on days 1, 3, 5, and 7 after IVIG for the first 3 weekly doses.
the
Thereafter
next
sera
were
collected
weekly
before
dose.
Conditioning regimens for BMT consisted body irradiation (450-1200 cGy) plus single varying combinations of cyclophosphamide,
sine
arabinoside,
fully
described
and
as
Gammaglobulin
Gammagard
(Baxter-Travenol)
is produced and
by ion ex-
75.7% IgG1, IgG4 #{149}8 J has a titer of
contains
IgG2, 4.6% IgG3, and 0.4% to CMV by hemagglutination
according
to the
manufacturer.
ELISA Sera were collected and stored frozen studied. IgG antibodies were measured
method
(Diamedix,
manufacturer. ber of gammagard
Miami,
Ten-fold was
at -70#{176}C until by an ELISA
FL) as described
by the
dilutions included
of a single lot numas a standard curve run; the CMV titer of this standard was 1:3300 (log10 = 3.52 ± 0.1, mean ± SD
in each test approximately of 10 determinations). serum
was
The
interpolated
sera from each patient run, and all sera were ber of ELISA kits.
AL
the
titer
from
were tested
the
of each
individual
standard
curve.
All
tested in the same test with the same lot num-
Statistical
the
data
analysis,
converted to ffg/mL based on the The plasma concentration profiles open one-compartment body model travenous injections9 using equation Cp
=
D/Vd*(1_e_*k8*)/(1
-
titers
were
standard curves. were fitted to an after multiple in1, e_k0*r)*e_k*t
[1]
where Cp is the plasma concentration, D the dose, Vd the volume of distribution, n the number of doses, ke
1152
5
J ClIn Pharmacol
constant,
r the
dosing
interval
Methods
within the
each
dose
calculated
dose and
regimen.
half-life
varied randomly coefficient was group weeks
To for
from week calculated
between 2 and 3.
Administration
weeks
were comthe two dosdifferences
determine
each
whether
individual
patient
to week, the correlation for all patients in each 1 and
2, weeks
1 and
3,
1991;31:1151-1154
of 500
mg/kg
gammagard
led
to
a
marked rise in CMV antibody level in all CMV seronegative patients. The average peak on the day after the first IVIG dose was 3.5 ± 1.4 mg/mL (gammagard) which rose to 5.5 ± 2.6 mg/mL after the third dose. Corresponding peak CMV antibody titers were (log10) 2.39 ± 0.10, and 2.59 ± 0.21. For those patients receiving 250 mg/kg gammagard, the peak levels were 2.6 ± 0.7 mg/mL, and 3.4 ± 1.2 mg/mL after the first
and
third
peak first
CMV titers 2.3 and third weekly
doses,
respectively, ±
and
0.12
doses,
the
corresponding
and 2.4 ± 0.15 after the respectively. The peak
titers after the 500 mg/kg dose were significantly higher than those after the 250 mg/kg dose, P 0.02 for each of the first 3 weeks. Plasma concentration profiles for the two doses shown in Figure 1. For the patients receiving
mg/kg, the elimination lated to be 0.111 ± 0.017 half-life of 6.2 days. The 0.61 tion
pharmacokinetic
rate
Serum CMV antibody titers and half-lives pared by t test for group means between ing regimens, and by t-test using paired
0.135
Pharmacokinetics For
elimination
and t the time after the last dose was given. The data was fitted using nonlinear regression analysis.1#{176} Half-life was calculated as ln 2/k8, total body clearance as ke*Vd.
RESULTS
chromatography
19.3% 1:1024
mustard
elsewhere.7
Intravenous
change
L-phenylalanine
of total agent or cyto-
ET
d1
± 0.014
L/kg,
and
rate
constant
d
which
volume the
total
are
500 calcu-
ke was corresponds
to a
of distribution
was
body
was
clearance
mL/hr/kg. For the 250 mg/kg dose, the eliminarate constant k8 was found to be 0.113 ± 0.019 which
responds
to a half-life
of 6.1
days.
The
vol-
ume of distribution was 0.100 ± 0.011 L/kg, and the total body clearance was 0.46 mL/hr/kg. As can be seen from Figure 1, no significant accumulation could be observed in the plasma concentrations after 6 weeks, so that a one compartment body model was sufficient to describe the observed data (solid lines). The half-lives were not statistically different between the two doses, nor were they statistically different after the different weekly doses. Calculated
PHARMACOKINETICS
OF WIG
AFTER
BMT
were based only on levels measured in CMV seronegative patients, so that residual antibody production after the initial conditioning regimen did not influence the results. Further, there was no substantial -1 E change in the conditioning regimen between the two N E studies. In addition, in the previous study, the halflife of total IgG among those patients who received C 0 no blood products in the week after the first IVIG 4-, (0 infusion was calculated to be between 5 to 10 days, L 4-, C depending on the assumption one makes about residSi U ual IgG production. Because the current study is subC 0 C-) stantially larger and because both dosing regimens were found to have the same half-life, the current findings are likely to reflect the true half-life of gammagard in BMT patients. time (days) There is no clear explanation for the rapid half-life of IVIG in BMT patients. In animal models, the catabolism of immunoglobulins has not been increased by Figure. Mean plasma concentrations (± SD) of intravenous immucorticosteroids, nitrogen mustard, or 6-mercaptopuno globulin (WIG) after weekly administration of 250 mg/kg (#{149}) rine. Although it is true that immunoglobulin halfand 500 mg/kg (O)to patients for 6 weeks. The points represent the experimentally measured concentrations, the line shows the prelife is accelerated under conditions in which immudicted concentration profile. noglobulin levels are elevated either passively or secondary to disease, the magnitude of this effect is -I
small
half-lives after each weekly dose did atically for each individual patient, statistically significant correlation vidual patient’s IVIG half-life after ond weekly doses, or between the the second and third. Efficacy of IVIG was not assessed will be reported fully elsewhere.
not vary i.e., there between the first first and in this
systemwas no an indiand secthird, or
study
and
DISCUSSION This present study not only obtained an estimate of the elimination half-life, but also quantitated other pharmacokinetic parameters such as volume of distribution and clearance. For these calculations, it was necessary to convert the measured titers in dose-related concentrations. The volume of distribution of 0.1 to 0.13 L/kg is small indicating only modest extravascular distribution of IVIG. This is not surprising considering the large molecular weight of IVIG. Total body clearance is small (0.46-0.61 L/hr/ kg) and results in a half-life of 6 days. In our previous study, the half-life of IVIG (sandoglobulin) was 3.4 ± 2.0 days after the first dose of IVIG and rose to 6.1 ± 5.1 days after the fifth dose.6 In the current study using gammagard, we found that the half-life was essentially constant over the first three weekly IVIG doses. In both studies, the data
ONCOLOGY/IMMUNOTHERAPY
at the
concentration
range
involved
in
these
studies. Thus, in our study of sandoglobulin, after a 500 mg/kg dose, total immunoglobulin levels were raised from a mean of 818 ± 219 mg/dl to 1468 ± 213 mg/dl among ten patients who received no other blood products at that time.6 At this level of increased immunoglobulin concentration, the half-life would only be expected to decrease from 22 days to the range of 18 to 20 days.11 Shibata et al. measured the half-life of anti-Hb5 after passive administration to Hb8 negative subjects, and showed a biphasic curve, with the first phase having a half-life of 135 to 152 hours, and a second phase of 17 to 24 days.12 The rapid half-life of the first phase was attributed to the time of distribution between the intraand extravascular compartments. However, if the observed IVIG half-life of approximately 6 days in BMT patients were simply due to distribution, we would have expected accumulation from the second to the sixth dose in excess of those observed and predicted by the one-compartment model. We conclude that the half-life of IVIG in BMT patients is rapid compared with that in normal subjects and that weekly dosing is optimal until efficacy data suggest otherwise.
The authors thank the staffs of the Shands Hospital Diagnostic Virology Laboratory, and Bone Marrow Transplant Unit for their generous support.
1153
RAND
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5
AL
Rand KH, Houck H, Ganju A, et al: Pharmacokinetics of cytomegalovirus specific IgG antibody following intravenous immunoglobulin in bone marrow transplant patients. Bone Marrow Trans p1 1989;4:679-683. 6.
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