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

REFERENCES 1. Berkman SA, immunaglobulins.

Lee ML, Gale RP: Clinical uses Ann Intern Med 1990:112:278-292.

of intravenous

4. Hagenbeek A, Brummelhuis HGI, Donkers A, et al: Rapid clearance of cytomegalovirus-specific IgG after repeated intravenous infusions of human immunoglobulin into allogenic bone marrow transplantation recipients. I Infect Dis 1987;155:897-902. 5. Bosi A, Enrichetta DM, Guidi 5, et al: Kinetics of anti-CMV antibodies after administration of intravenous immunoglobulins to bone marrow transplant recipients. Haematologica 1990; 75: 109-112.

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.

2. Sullivan KM, Kenneth MD, Kopecky J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 1990:323(1 1):705-712. 3. Winston DJ, Ho WG, Lin CH, et al: Intravenous immunoglobulin for prevention of interstitial pneumonia after bone marrow transplantation. Ann Intern Med 1987:106:12-18.

1154

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J Clln Pharmacol

1991;31:1151-1154

7. Elfenbein characterization transplantation. Beard therapy.

8.

CJ,

Ashkenazi YJ, Barth KC: Further phenotypic of T cells after human allogeneic bone marrow Transplantation 1985:39:97-102.

U, Ferrante A: Aspects of immunoglobulin Pediatr Infect Dis J 1990;9:S54-S61.

Gibaldi M, Perrier Marcel Dekker, 1982.

9.

10.

MINSQ,

Waldmann Progr. Allergy 11.

D: Phormocokinetics

MicroMath,

Salt

TA, Strober 1969:13:1-110.

12. Shibata Y, Baba passively transferred

Lake

City:

W: Metabolism

M, Kuniyuki, antibodies

2nd

replacement ed.

New

York:

Utah. of immunoglobulins.

M: Studies on the retention of in man. Vox Sang 1983:45:77-82.

Pharmacokinetics of intravenous immunoglobulin (Gammagard) in bone marrow transplant patients.

The pharmacokinetics of an intravenous immunoglobulin (IVIG), Gammagard (Baxter Healthcare Corp., Glendale, CA), were measured in 31 cytomegalovirus (...
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