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Product Equivalence Study Comparing the Tolerability, Pharmacokinetics, and Pharmacodynamics of Various Human Immunoglobulin‐G Formulations
Author(s) -
Andresen Irmgard,
Kovarik John M.,
Spycher Martin,
Bolli Reinhard
Publication year - 2000
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700022009477
Subject(s) - pharmacokinetics , medicine , pharmacodynamics , tolerability , bioequivalence , adverse effect , pharmacology , immunogenicity , volume of distribution , nicotinamide , antibody , whole blood , gastroenterology , immunology , chemistry , biochemistry , enzyme
In this randomized, double‐blind, parallel‐group study, a commercially available human immunoglobulin‐G product, IVIG, was compared with two test formulations: (1) IVIG‐N, which is a nanofiltered formulation of IVIG, and (2) IVIG‐L, which is a nanofiltered, liquid, ready‐for‐use IgG formulation containing nicotinamide, L‐proline, and L‐isoleucine as stabilizers. Three groups of 10 healthy subjects each received a single 0.6 g/kg dose of one of the 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 leukocytes and TNF‐α. A blood sample was taken at 6 months for a viral safety check. Administrations were generally well tolerated with only one reference IVIG infusion stopped prematurely due to headache. The IgG C max and AUC over the 6‐week blood sampling period from both test formulations satisfied equivalence criteria compared with the reference formulation. In subjects receiving IVIG‐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 mmol/L, which are below those reported to cause adverse events. During the infusion of IVIG, leukocyte counts initially declined from a baseline of 5.7 ± 1.1 × 10 9 /L to 3.7 ± 0.8 × 10 9 /L at 2 to 4 hours and returned to baseline by 24 hours. TNF‐α levels, reflecting activation of the monocyte‐macrophage system by the infused IVIG, rose from a baseline of13± 4 pg/mL to a peak of 272 ± 324 pg/mL at 2 to 4 hours and returned to baseline by 24 hours. These patterns were generally similar for the test formulations, with the exception that the increase in TNF‐α levels was dampened for IVIG‐N, although this was not statistically significant. There was no evidence of immunogenicity or viral transmission from any of the formulations. 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.