Product equivalence study comparing the tolerability, pharmacokinetics, and pharmacodynamics of various human immunoglobulin-G formulations

In this randomized, double-blind, parallel-group study, a commercially avai lable human immunoglobulin-G product, IVIG, was compared with two test form ulations: (1) IVIG-N, which is a nanofiltered formulation of IVIG, and (2) IVIG-L, which is a nanofiltered, liquid, ready-for-use IgG formulation cont aining nicotinamide, L-proline, and L-isoleucine as stabilizers. Three grou ps of 10 healthy subjects each received a single 0.6 g/kg dose of one of th e formulations infused over 3.5 to 6.8 hours, depending on the total volume to be infused. Blood samples were obtained over a 6-week period to assess pharmacokinetics, immunogenicity, and the pharmacodynamic effects on leukoc ytes and TNF-alpha. A blood sample was taken at 6 months for a viral safety check. Administrations were generally well tolerated with only one referen ce IVIG infusion stopped prematurely due to headache. The IgG C-max and AUC over the 6-week blood sampling period from both test formulations satisfie d equivalence criteria compared with the reference formulation. In subjects receiving NTG-L, peak concentrations of the stabilizer nicotinamide ranged from 0.34 to 0.47 mmol/L and of nicotinamide-N-oxide from 0.03 to 0.04 mmo l/L, which are below those reported to cause adverse events. During the inf usion of IVIG, leukocyte counts initially declined from a baseline of 5.7 /- 1.1 x 10(9)/L to 3.7 +/- 0.8 x 10(9)/L at 2 to 4 hours and returned to b aseline by 24 hours. TNF-alpha levels, reflecting activation of the monocyt e- macrophage system by the infused IVIG, rose from a baseline of 13 +/- 4 pg/mL to a peak of 272 +/- 324 pg/mL at 2 to 4 hours and returned to baseli ne by 24 hours. These patterns were generally similar for the test formulat ions, with the exception that the increase in TNF-alpha levels was dampened for IVIG-N, although this Mas not statistically significant. There was no evidence of immunogenicity or viral transmission from any of the formulatio ns. Hence, these three formulations were generally well tolerated, yielded similar systemic exposure to IgG over a 6-week period after administration, and did not give rise to immunogenicity or viral safety concerns. (C) 2000 the American College of Clinical Pharmacology.