Plasma concentration of hGH and anti-hGH antibodies after subcutaneous administration of hGH for 3 weeks to immunosuppressed pigs.
OBJECTIVE
The objective of the present study was to evaluate the dosing regimen of immunosuppressants necessary to avoid the formation of anti-hGH antibodies in a pig model.


METHODS
Sixteen pigs were divided into four groups.


METHODS
Three different immunosuppressive treatments were tested (group 1: Control (no treatment); group 2: 10 mg; group 3: 20 mg; and group 4: 40 mg cyclosporine; combined with 2 mg azatioprine and 2 mg prednisolone p.o./kg/day). The treatments were given from days -7 to 22. All groups were dosed subcutaneously (s.c.) with 0.5 mg hGH/kg once daily from days 1 to 22. On the first and the last days of dosing blood samples were collected to describe the hGH concentration versus time profile. Before dosing and on days 5, 10, and 15 blood samples were collected for measuring hGH antibody formation.


RESULTS
A dose-dependent decrease in white blood cell counts was observed in all immunosuppressive-treated groups. Groups 1 and 2 produced antibodies against hGH during the 22 days of dosing while the formation of antibodies was suppressed in groups 3 and 4. In the control group and group 2 the pharmacokinetic parameters of hGH were influenced by the formation of anti-hGH antibodies. In groups 3 and 4, the pharmacokinetic parameters were comparable on the first and the last day of dosing.


CONCLUSIONS
The formation of anti-hGH antibodies influenced the pharmacokinetics of hGH in pigs, but it could be prevented by immunosuppressive therapy. From the present experiment, a dose of 20 mg cyclosporine, 2 mg azatioprine, and 2 mg prednisolone p.o./kg/day was able to prevent the pigs from producing antibodies without having severe adverse effects. This model may by useful in future experiments using sustained release formulations of hGH, and possibly for other compounds that may induce antibody production in pigs.
Agersø
H
H
Department of Pharmacokinetics, Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark. hkag@novo.dk
Wilken
M
M
Drustrup
J
J
Haahr
P M
PM
Jørgensen
K D
KD
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D019540:Area Under Curve; D001323:Autoantibodies / Q000032:analysis*; D001379:Azathioprine / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D007958:Leukocyte Count / Q000187:drug effects; D011239:Prednisolone / Q000008:administration & dosage; D013552:Swine
D001323:Autoantibodies; D007166:Immunosuppressive Agents; D019382:Human Growth Hormone; D016572:Cyclosporine; D011239:Prednisolone; D001379:Azathioprine