Pharmacokinetics and safety of a novel anti-HBs-enriched immunoglobulin in healthy volunteers after subcutaneous and intramuscular administration

Abstract

In patients having undergone orthotopic liver transplantation, the combination of lamivudine plus human hepatitis B immunoglobulin (HBIg), usually given by the intravenous (i.v.) route, is the most effective prophylaxis against the recurrence of the hepatitis B virus [7]. The availability of a subcutaneous (s.c.) preparation would enable these patients to self-administer their required HBIg dose and thereby provide savings in health care costs as a result of a reduced number of visits to the physician [3]. However, when the standard i.v. preparations are used, a dose of approximately 2000 IU, corresponding to a volume of 40 ml, has to be given every 4–6 weeks. To be suitable for s.c. application, the HBIg preparation must contain a higher concentration per milliliter of the antibody to hepatitis B surface antigen (anti-HBs). We therefore investigated the tolerability and pharmacokinetics of the novel HBIg BT088 (manufacturer Biotest AG, Dreieich, Germany), which contains 635 IU anti-HBs/ ml [1], in male and female healthy volunteers after s.c. and intramuscular (i.m.) administration, since both application routes may offer advantages for patients. After approval of the protocol by the local ethics committee, written informed consent was obtained from each volunteer enrolled into this open, randomised, parallel group study. Thirty healthy volunteers (15 females) with baseline anti-HBs concentrations below 0.002 IU/ml were enrolled; they received a single dose of BT088 at 30 IU/kg body weight either s.c. (SC-Group) or by the i.m. route (IM-Group). Blood samples for determination of anti-HBs serum concentrations were drawn before the administration of BT088, and at specified time points following its administration: 1, 3 and 6 h (first day), 24 h (day 2) and on days 3, 5, 8, 12, 18, 22, 29, 43, 57 and 71. Measurements of antiHBs concentrations were performed in duplicate using an enzyme-linked immunoassay (AUSAB, Abbott, Germany) as described previously [9, 10]. Pharmacokinetic parameters for anti-HBs were calculated using WINNONLIN PROFESSIONAL ver. 4.1 (Pharsight, Cary, N.C.) as in earlier studies [10]. For comparison with pharmacokinetic parameters obtained in previous trials [9, 10], Cmax and AUC0−∞ were further dose-normalised for a dose of 1000 IU as described earlier [10]. Descriptive statistical analyses (mean, standard deviation, median) were performed using the SAS System for Windows, release 8.2 (SAS Institute, Cary. N.C.). The pharmacokinetic parameters are given in Table 1. Protective levels above 0.1 IU/ml [2] were achieved as early as 20.4±7.5 h (median: 23.8 h; range: 6.0–24.2 h) after s.c. application and at 19.9±8.2 h (median: 24.0 h; range: 1.0–24.1 h) after i.m. injection. No serious adverse events occurred during the study, and only mild reactions at the injection site appeared in four volunteers. Comparable serum concentrations were obtained over the observation period using both administration routes. The mean terminal elimination half-lives (t1/2el) of 23 days correspond to that of normal human IgG [5] and are in accordance with data of HBIg for i.v. administration in healthy volunteers [9] and in patients with multiple myeloma or chronic leukaemia [10]. Comparable halflives were obtained after i.m. administration of HBIg of P. A. Thurmann (*) . J. Szymanski . S. Haffner . U. Tenter Philipp Klee-Institute of Clinical Pharmacology, HELIOS Klinikum Wuppertal, University Witten/Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany e-mail: pthuermann@wuppertal.helios-kliniken.de Tel.: +49-202-8961851 Fax: +49-202-8961852