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Purpose: This phase 3, multicenter, open-label, randomized, two-period, crossover bioequivalence trial evaluated the safety, tolerability, and pharmacokinetics of intravenous immunoglobulins (IVIGs) Gammaplex 5% and Gammaplex 10% in 33 adults and 15 children with primary immunodeficiency diseases (PIDs). Methods: Eligible adults received five Gammaplex 5% infusions followed by five Gammaplex 10% infusions, or vice versa, stratified by a 21- or 28-day dosing regimen. Pediatric subjects received five Gammaplex 10% infusions only. Results: The primary objective, to demonstrate the bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval, was met based on the Gammaplex 10%/Gammaplex 5% ratio of area under the concentration versus time curve (AUC) values. Throughout the study, total immunoglobulin G trough levels were well maintained, with total values generally ≥600 mg/dL (minimum level for study inclusion). At the dosing schedules and infusion rates used in this study, safety and tolerability were comparable and acceptable in adult and pediatric PID subjects treated with Gammaplex 10% and 5%. Conclusions: In this study, the first direct comparison of 5% IVIG and 10% IVIG products in PID subjects, the pharmacokinetic analysis demonstrated bioequivalence of Gammaplex 10% and Gammaplex 5% at the 28-day dosing interval. The Gammaplex 10% formulation was safe and well tolerated in pediatric and adult PID subjects. Based on the results from this bridging study in PID subjects, Gammaplex 10% could be expected to have a therapeutic effect similar to the licensed Gammaplex 5%, which has demonstrated efficacy and tolerability in patients with PID and idiopathic thrombocytopenic purpura. [ABSTRACT FROM AUTHOR]

Purpose: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. Methods: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. Results: Eighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years. Conclusions: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD. [ABSTRACT FROM AUTHOR]

Purpose: Immune globulins for IgG supplementation have been produced for over 35 years with essentially no differentiating features regarding their specific antibody composition. Furthermore, the compositions of plasma donor pools used for IG manufacturing are not standardized. While all immune globulin products meet the specifications set by the US FDA for antibodies to pathogens like measles and polio, they have variable levels of antibodies to other important viruses and infectious pathogens, particularly respiratory syncytial virus (RSV). Methods: An IVIG was developed that satisfies the requirements for treating patients with primary immune deficiency disease (PIDD) and also has standardized elevated levels of RSV neutralizing antibodies (RI-002). Plasma donors who have naturally occurring high circulating levels of neutralizing anti-RSV antibody were selected as the source for manufacturing IVIG to treat patients with PIDD to prevent serious bacterial infections. While the introduction of the monoclonal antibody Palivizumab has had a dramatic impact in diminishing the burden of RSV disease in the pediatric population, it does not meet the standards for replacing the deficient immune compartments of patients with PIDD. Results: Fifty-nine patients with PIDD at 9 different sites across the US were enrolled in this study and received regular infusions of RI-002 over the course of 1 year. Conclusions: There were zero serious bacterial infections, thus meeting the primary endpoint for this trial. The secondary endpoints including days missed from work due to infection, unscheduled visits to the physician, and days of hospitalization due to infection compared favorably to published reports of other IVIG products. [ABSTRACT FROM AUTHOR]

Background: Patients with immunodeficiency diseases require lifelong treatment with immunoglobulin (Ig), yet few studies have vetted dosing strategies and effectiveness of Ig in older patient populations. Patients requiring subcutaneous (SC) Ig (SCIG) typically start with intravenous dosing before transitioning to SCIG weekly maintenance. In this retrospective review, we investigated an alternate strategy with higher initial SC doses among an older patient population with antibody deficiency syndromes. Findings: Records of 13 patients (mean age, 70 years) with antibody deficiencies who were naive to treatment with Ig were assessed. SCIG (Vivaglobin® [Immune Globulin Subcutaneous (Human), 16% Liquid] or Hizentra® [Immune Globulin Subcutaneous (Human), 20% Liquid]) was given twice weekly (100 mg/kg) for 2 weeks, followed by weekly (100 mg/kg) administration The mean pretreatment IgG level was 460 mg/dL; at 1, 3, and 6 months after SCIG initiation, mean IgG serum levels were 852, 907, and 943 mg/dL, respectively. Maintenance doses were unchanged during 6 months of follow-up. All patients remain on SCIG (median, 44 months). One patient developed sepsis/cholangitis unrelated to treatment 3 months after starting SCIG; no other serious bacterial infections were reported. Conclusions: Initiation of SCIG by doubling the maintenance dose over 2 weeks may be a well-tolerated and effective option for patients with antibody deficiencies requiring Ig replacement, especially among older patients. [ABSTRACT FROM AUTHOR]

Introduction: An investigational 10% liquid intravenous immunoglobulin (IVIG) was studied in 63 patients with primary immunodeficiency (PID) at 15 study sites. Methods: Patients were treated every 3 or 4 weeks with 254-1029 mg/kg/infusion of IVIG. Results: Overall, Biotest-IVIG infusions were well tolerated. The proportion of infusions that were associated with adverse events during infusion, and up to 72 h after infusion, including those unrelated to study product, was 27.7% with an upper 95% confidence limit ≤30.6%. Two serious bacterial infections (SBIs) were observed resulting in a serious bacterial infection rate of 0.035 per person per year and an upper one-sided 99% confidence limit of ≤0.136 SBI/patient/year. The number of days of work or school missed due to infection were relatively low at 2.28 days/patient/year. Two patients were hospitalized for infection producing a rate of 0.21 hospitalization days/patient/year. The IgG half-life was approximately 30 days with variation among individuals. Conclusions: Pharmacokinetic parameters of specific antibody activities were essentially the same as those of total IgG. Biotest-IVIG is safe and effective in the treatment of PID. [ABSTRACT FROM AUTHOR]

Background and Objectives: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra®), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen®). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy. Methods: This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6-75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agamma-globulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (Ctrough) values ≥>5 g/L. IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients' previous doses, based on the results obtained in a Vivaglobin® study and due to an FDA request. After run-in, each patient's dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously. Results: Eighteen patients completed the study. Mean IgPro20:IgPro10 dose ratio (dose adjustment co-efficient) was 1.53 (range 1.26-1.87). The resulting mean AUCs were 105.6g · day/L for IgPro20 versus 103.2 g · day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18-1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective. Conclusion: Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under- protection but vary too widely to be considered measures of equivalence. Trial registration number (clinicaltrials.gov): NCT00419341 [ABSTRACT FROM AUTHOR]

multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3-77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease. [ABSTRACT FROM AUTHOR]

The tolerability of L-proline-stabilized Privigen®, a new 10% liquid immunoglobulin for intravenous administration, was assessed at high infusion rates in a Phase III, open-label, single-arm, multicenter study in 45 patients with primary immune deficiencies. Maximum infusion rates were not assigned prospectively. For analysis, patients were grouped according to maximum infusion rate in a low infusion rate group (8 mg/kg/min) and high infusion rate group (12 mg/kg/min). Twenty-three patients, selected at the investigators’ discretion for the high infusion rate group based on their good tolerability, tolerated Privigen® at 12 mg/kg/min with no increase in temporally associated adverse events (AEs) above the level they had experienced at 8 mg/kg/min. The proportion of infusions with temporally associated AEs in these patients was 0.079 [97.5% confidence interval (CI) 0.114] compared to 0.211 (97.5% CI 0.267) in the low infusion rate group. The most frequent AE was headache. Thus, selected patients tolerate Privigen® at high infusion rates. [ABSTRACT FROM AUTHOR]

Flebogamma® 10% DIF represents an evolution of intravenous immune globulin from the previous 5% product to be administered at higher rates and with smaller infusion volumes. Pathogen safety is enhanced by the combination of multiple methods with different mechanisms of action. The objective of this study as to evaluate the efficacy, pharmacokinetics, and safety of Flebogamma® 10% DIF for immunoglobulin replacement therapy in primary immunodeficiency diseases (PIDD). Flebogamma® 10% DIF was administered to 46 subjects with well-defined PIDD at a dose of 300–600 mg/kg every 21–28 days for 12 months. Serious bacterial infection rate was 0.025/subject/year. Half-life in serum of the administered IgG was approximately 35 days. No serious treatment-related adverse event (AE) occurred in any patient. Most of the potentially treatment-related AEs occurred during the infusion, accounting for 20% of the 601 infusions administered. Flebogamma® 10% DIF is efficacious and safe, has adequate pharmacokinetic properties, and is well-tolerated for the treatment of PIDD. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. Objective: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. Methods: In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. Results: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. Conclusion: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates. [ABSTRACT FROM AUTHOR]

Abstract: Intravenous immunoglobulin (IVIg) is used in treating immunodeficiencies and autoimmune or inflammatory disorders. As manufacturing processes and storage can alter IgG molecules, pharmacokinetic assessments are important for new preparations. Thus, we studied pharmacokinetics of IgPro10, a new 10% liquid IVIg product stabilised with l-proline, in patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA). Patients received IgPro10 for ≥4 months (median dose of 444mg/kg, at 3- or 4-week intervals). Median total IgG serum concentrations increased from 10.2g/l pre-infusion to 23.2g/l at infusion end. Serum IgG concentrations decreased in a biphasic manner; median terminal half-life was 36.6 days. Median half-lives were 33.2 for IgG1, 36.3 for IgG2, 25.9 for IgG3 and 36.4 days for IgG4. Specific antibody concentrations (anti-CMV, anti-Hemophilus influenzae type B, anti-tetanus toxoid and anti-Streptococcus pneumoniae) decreased with median half-lives of 22.3–30.5 days. IgPro10 pharmacokinetics were similar in patients with CVID and XLA, although patients with CVID showed higher levels of anti-tetanus and anti-S. pneumoniae antibodies than patients with XLA, suggesting residual specific antibody production. IgPro10 pharmacokinetics fulfilled expectations for and were similar to intact IgG products. Administration of IgPro10 at 3- or 4-week intervals achieved sufficient plasma concentrations of total IgG, IgG subclasses and antibodies specific to important pathogens. [Copyright &y& Elsevier]