title: Efficacy, tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies.
abstract: OBJECTIVE
  A nanofiltration step with the capacity to reduce blood-borne pathogens was introduced into the manufacturing process of intravenous immunoglobulin (IVIG). In order to demonstrate the efficacy, safety and pharmacokinetics of the modified product, we conducted Phase II/III studies comparing the nanofiltered IVIG (IVIG-N) with its parent product, Sandoglobulin, in patients with chronic immune thrombocytopenic purpura (ITP) and primary immunodeficiencies (PID).
  
  
  METHODS
  Patients with ITP (n = 27) with platelet counts of < 20 x 10(9)/l were treated with Sandoglobulin or IVIG-N infusions at a dose of 0.4 g/kg body weight on five consecutive days. The primary efficacy end-point was the number of patients with an increase in platelet counts to > 50 x 10(9)/l. Secondary end-points were time to and duration of response, and regression of bleeding. Patients with PID (n = 36) were treated for 6 months with Sandoglobulin or IVIG-N at doses of 0.2-0.8 g/kg, infused at 3- or 4-week intervals. The primary end-point was the number of days absent from school/work. Secondary end-points were hospitalization, use of antibiotics and feeling of well-being. In both studies, tolerability was assessed by recording of adverse events and laboratory determinations. Viral safety was ascertained by serology supplemented with nucleic acid detection methods. Pharmacokinetics were analysed in patients with PID using serum concentration-time data for immunoglobulin G (IgG), and IgG antibodies to hepatitis B surface antigen (anti-HBsAg).
  
  
  RESULTS
  In the ITP study, the primary end-point was met by 12/16 patients on IVIG-N and by 10/10 patients on Sandoglobulin (P = 0.123). A shift towards lesser bleeding intensity was seen in both groups. In the PID study, seven of 18 patients on IVIG-N and six of 16 patients on Sandoglobulin missed days at work/school, with monthly mean absences of 0.4 and 0.5 days (P = 0.805). The feeling of well-being was comparable in both groups. In the ITP study, adverse events with a causal relationship to medication were suspected in six patients on IVIG-N and in seven on Sandoglobulin. In the PID study, three patients on IVIG-N and two on Sandoglobulin experienced possible drug-related adverse events. In both studies, serological and polymerase chain reaction (PCR) tests gave evidence for virus safety. Pharmacokinetics showed constant peak and trough serum IgG levels in all patients, indicating almost steady-state conditions for both formulations. The overall half-life (t1/2) for total IgG was 33 +/- 17 days in the IVIG-N arm and 25 +/- 16 days in the Sandoglobulin arm; for anti-HBsAg t1/2, values were 17 +/- 7 and 17 +/- 9 days, respectively.
  
  
  CONCLUSIONS
  IVIG-N is efficacious, well tolerated and safe in patients with ITP and PID. Its pharmacokinetic properties were comparable to those of Sandoglobulin.
authors.affiliation: Department of Haematology and Oncology, University Hospital, Halle, Germany.
authors.forename: H H
authors.initials: HH
authors.lastname: Wolf
authors.forename: S V
authors.initials: SV
authors.lastname: Davies
authors.forename: M
authors.initials: M
authors.lastname: Borte
authors.forename: M T
authors.initials: MT
authors.lastname: Caulier
authors.forename: P E
authors.initials: PE
authors.lastname: Williams
authors.forename: H V
authors.initials: HV
authors.lastname: Bernuth
authors.forename: W
authors.initials: W
authors.lastname: Egner
authors.forename: I
authors.initials: I
authors.lastname: Sklenar
authors.forename: C
authors.initials: C
authors.lastname: Adams
authors.forename: P
authors.initials: P
authors.lastname: Späth
authors.forename: A
authors.initials: A
authors.lastname: Morell
authors.forename: I
authors.initials: I
authors.lastname: Andresen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003257:Consumer Product Safety; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000493:pharmacokinetics* / Q000592:standards* / Q000627:therapeutic use; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000150:complications / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014462:Ultrafiltration; D014777:Virus Diseases / Q000517:prevention & control / Q000635:transmission
chemical_list: D016756:Immunoglobulins, Intravenous; D014409:Tumor Necrosis Factor-alpha