Polyvalent Human Immune Globulin: A Prospective, Open-Label Study Assessing Anti-Hepatitis A Virus (HAV) Antibody Levels, Pharmacokinetics, and Safety in HAV-Seronegative Healthy Subjects

Martin Kankam, Rhonda Griffin, Jeffrey Price, Josée Michaud, Wei Liang, Mariona Bassas Llorens, Ana Sanz, Bradley Vince, David Vilardell, Martin Kankam, Rhonda Griffin, Jeffrey Price, Josée Michaud, Wei Liang, Mariona Bassas Llorens, Ana Sanz, Bradley Vince, David Vilardell

Abstract

Background: Analytical data suggesting that immunoglobulin given intramuscularly (IGIM) may have reduced protection against hepatitis A virus (HAV) infection led to an update in the recommended IGIM dose (0.2 ml/kg).

Methods: This prospective, open-label, single-arm clinical study evaluated whether a single 0.2 ml/kg dose of IGIM provided protective levels of anti-HAV antibodies (≥ 10 mIU/ml for up to 60 days) in HAV-seronegative healthy adults.

Results: Of the 28 subjects enrolled and dosed, 26 (93%) completed the study. Mean uncorrected anti-HAV antibody titers peaked at 109 mIU/ml on day 5 and stayed above 10 mIU/ml through day 60 (N = 26). The mean uncorrected anti-HAV antibody titers had a median Tmax of 95.33 h, a mean Cmax of 118 mIU/ml, and a mean observed Thalf of 63.3 days; baseline-corrected titers had a median Tmax of 95.33 h, a mean Cmax of 114 mIU/ml, and a mean observed Thalf of 47.1 days (N = 27). All subjects (28/28) experienced at least 1 treatment-emergent adverse event (TEAE), with a total of 83 TEAEs reported; none was serious, and 96% (80/83) resolved without sequelae. Most (63%) events judged definitely and possibly related to study treatment involved localized pain due to intramuscular injections. There were no serious adverse events and no deaths or discontinuations due to TEAEs.

Conclusions: A single 0.2 ml/kg dose of IGIM provided protective anti-HAV levels for at least 60 days, with acceptable safety and tolerability profiles in healthy subjects. Uncorrected and baseline-corrected pharmacokinetic findings were similar and consistent with the corresponding sampling points in previous research.

Trial registration: ClinicalTrials.gov Identifier, NCT03351933.

Keywords: Efficacy; Hepatitis A virus; Infectious diseases; Intramuscular immunoglobulin; Pharmacokinetics; Safety; Tolerability.

Figures

Fig. 1
Fig. 1
Disposition of subjects. a Discontinued on day 54. b Discontinued on day 20
Fig. 2
Fig. 2
Mean serum uncorrected concentration-time profile of anti-HAV antibody following a single 0.2 ml/kg dose of IGIM on linear (a) and semi-log (b) scales (PK population). HAV hepatitis A virus, IGIM immunoglobulin via intramuscular injection. The blue reference line is set at the protective threshold of 10 mIU/ml
Fig. 3
Fig. 3
Mean serum baseline-corrected concentration-time profile of anti-HAV antibody following a single 0.2 ml/kg dose of IGIM on linear (a) and semi-log (b) scales (PK population). HAV hepatitis A virus, IGIM immunoglobulin via intramuscular injection. The blue reference line is set at the protective threshold of 10 mIU/ml

References

    1. Krugman S, Giles JP. Viral hepatitis. New light on an old disease. JAMA. 1970;212(6):1019–1029. doi: 10.1001/jama.1970.03170190035005.
    1. Hepatitis A. Hepatitis A vaccines. Wkly Epidemiol Rec. 2000;75(5):38–44.
    1. GBD 2015 Mortality and Causes of Death Collaborators Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–1544. doi: 10.1016/S0140-6736(16)31012-1.
    1. Klevens RM, Miller JT, Iqbal K, Thomas A, Rizzo EM, Hanson H, et al. The evolving epidemiology of hepatitis a in the United States: incidence and molecular epidemiology from population-based surveillance, 2005–2007. Arch Intern Med. 2010;170(20):1811–1818. doi: 10.1001/archinternmed.2010.401.
    1. Fujiwara K, Yokosuka O, Ehata T, Saisho H, Saotome N, Suzuki K, et al. Association between severity of type A hepatitis and nucleotide variations in the 5' non-translated region of hepatitis A virus RNA: strains from fulminant hepatitis have fewer nucleotide substitutions. Gut. 2002;51(1):82–88. doi: 10.1136/gut.51.1.82.
    1. Chi H, Haagsma EB, Riezebos-Brilman A, van den Berg AP, Metselaar HJ, de Knegt RJ. Hepatitis A related acute liver failure by consumption of contaminated food. J Clin Virol. 2014;61(3):456–458. doi: 10.1016/j.jcv.2014.08.014.
    1. Yoshida Y, Okada Y, Suzuki A, Kakisaka K, Miyamoto Y, Miyasaka A, et al. Fatal acute hepatic failure in a family infected with the hepatitis A virus subgenotype IB: a case report. Medicine (Baltimore) 2017;96(35):e7847. doi: 10.1097/md.0000000000007847.
    1. Centers for Disease Control and Prevention. Hepatitis surveillance report no. 56, 1996. Available at: . Accessed 12 Mar 2020.
    1. Collier MG, Tong X, Xu F. Hepatitis A hospitalizations in the United States, 2002–2011. Hepatology. 2015;61(2):481–485. doi: 10.1002/hep.27537.
    1. Willner IR, Uhl MD, Howard SC, Williams EQ, Riely CA, Waters B. Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States. Ann Intern Med. 1998;128(2):111–114. doi: 10.7326/0003-4819-128-2-199801150-00006.
    1. Brown GR, Persley K. Hepatitis A epidemic in the elderly. South Med J. 2002;95(8):826–833. doi: 10.1097/00007611-200295080-00010.
    1. Chau TN, Lai ST, Tse C, Ng TK, Leung VK, Lim W, et al. Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A. Am J Gastroenterol. 2006;101(2):292–296. doi: 10.1111/j.1572-0241.2006.00416.x.
    1. Novak R, Bell B. Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travellers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Morb Mortal Wkly Rep. 2007;56(41):1080–1084.
    1. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep. 2006;55(RR-07):1–23.
    1. Nelson NP (2017) Hepatitis A. In: CDC Yellow Book 2018 Health Information for International Travel. Oxford University Press, New York
    1. Nelson NP. Updated dosing instructions for immune globulin (human) GamaSTAN S/D for hepatitis A virus prophylaxis. MMWR Morb Mortal Wkly Rep. 2017;66(36):959–960. doi: 10.15585/mmwr.mm6636a5.
    1. Nelson NP, Link-Gelles R, Hofmeister MG, Romero JR, Moore KL, Ward JW, et al. Update: recommendations of the Advisory Committee on Immunization practices for use of hepatitis A vaccine for postexposure prophylaxis and for preexposure prophylaxis for international travel. MMWR Morb Mortal Wkly Rep. 2018;67(43):1216–1220. doi: 10.15585/mmwr.mm6743a5.
    1. Liu JP, Nikolova D, Fei Y. Immunoglobulins for preventing hepatitis A. Cochrane Database Syst Rev. 2009;2:CD004181. doi: 10.1002/14651858.CD004181.pub2.
    1. Victor JC, Monto AS, Surdina TY, Suleimenova SZ, Vaughan G, Nainan OV, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med. 2007;357(17):1685–1694. doi: 10.1056/NEJMoa070546.
    1. Tejada-Strop A, Costafreda M, Dimitrova Z, Kaplan GG, Teo C. Evaluation of potencies of immune globulin products against hepatitis a. JAMA Intern Med. 2017;177(3):430–432. doi: 10.1001/jamainternmed.2016.9057.
    1. Prescribing information: GAMASTAN® [immune globulin (human)], solution for intramuscular injection. Available at: . Accessed 12 Mar 2020.
    1. Cohn EJ, Strong LE, et al. Preparation and properties of serum and plasma proteins; a system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc. 1946;68:459–475. doi: 10.1021/ja01207a034.
    1. Cohn EJ, Gurd FRN, Surgenor DM, Barnes BA, Brown RK, Derouaux G, et al. A system for the separation of the components of human blood: quantitative procedures for the separation of the protein components of human plasma1a, b, c. J Am Chem Soc. 1950;72(1):465–474. doi: 10.1021/ja01157a122.
    1. Oncley JL, Melin M, Richert DA, Cameron JW, Gross PM. The separation of the antibodies, isoagglutinins, prothrombin, plasminogen and β1-lipoprotein into subfractions of human plasma. J Am Chem Soc. 1949;71(2):541–550. doi: 10.1021/ja01170a048.
    1. Barnette D, Roth NJ, Hotta J, Cai K, Gall M, Hartwell R, et al. Pathogen safety profile of a 10% IgG preparation manufactured using a depth filtration-modified process. Biologicals. 2012;40(4):247–253. doi: 10.1016/j.biologicals.2012.04.003.
    1. Lebing W, Remington KM, Schreiner C, Paul HI. Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang. 2003;84(3):193–201. doi: 10.1046/j.1423-0410.2003.00285.x.
    1. Waldmann TA, Strober W, Blaese RM. Variations in the metabolism of immunoglobulins measured by turnover rates. In: Merler E, editor. Immunoglobulins: biologic aspects and clinical uses. Washington: National Academy of Sciences; 1970. pp. 33–51.
    1. Kroger AT, Duchin JS, Vázquez M. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices (ACIP). Available at: . Accessed 12 Mar 2020.
    1. Council of Europe . European pharmacopoeia. 8. Strasbourg: Council of Europe; 2015.
    1. Feinstone SM, Kapikian AZ, Purcell RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science. 1973;182(4116):1026. doi: 10.1126/science.182.4116.1026.
    1. Neefe JR, Stokes J., Jr An epidemic of infectious hepatitis apparently due to a water borne agent: epidemiologic observations and transmission experiments in human volunteers. JAMA. 1945;128(15):1063–1075. doi: 10.1001/jama.1945.02860320005003.
    1. Drake ME, Ming C. Gamma globulin in epidemic hepatitis: comparative value of two dosage levels, apparently near the minimal effective level. JAMA. 1954;155(15):1302–1305. doi: 10.1001/jama.1954.03690330006002.
    1. Viral Hepatitis and Liver Disease (1991) Proceedings of the 1990 international symposium on viral hepatitis and liver disease: contemporary issues and future prospects. Williams Wilkins, Baltimore.
    1. Zaaijer HL, Leentvaar-Kuijpers A, Rotman H, Lelie PN. Hepatitis A antibody titres after infection and immunization: implications for passive and active immunization. J Med Virol. 1993;40(1):22–27. doi: 10.1002/jmv.1890400106.
    1. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet. 1972;1(7762):1208–1212. doi: 10.1016/S0140-6736(72)90926-9.
    1. Jilma-Stohlawetz P, Reiter RA, Panzer S, Horvath M, Eppel W, Jilma B. Pharmacokinetics (PK) of S/D treated anti-D immunoglobulin after intramuscular injection in healthy volunteers: gender differences in PK. Transfus Apher Sci. 2005;33(2):135–140. doi: 10.1016/j.transci.2005.02.006.
    1. Filipponi F, Franchello A, Carrai P, Romagnoli R, De Simone P, Woodward MK, et al. Efficacy, safety, and pharmacokinetics of intramuscular hepatitis B immune globulin, Igantibe, for the prophylaxis of viral B hepatitis after liver transplantation. Dig Liver Dis. 2010;42(7):509–514. doi: 10.1016/j.dld.2009.09.005.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren