Title

Pharmacokinetic Study of ARALAST (Human Alpha1- PI)
Single-Dose, Double-Blind, Crossover Study to Evaluate the Pharmacokinetic Comparability of ARALAST Fraction IV-1 Alpha1-Proteinase Inhibitor (ARALAST Fr. IV-1) and ARALAST
  • Phase

    Phase 1
  • Study Type

    Interventional
  • Intervention/Treatment

    alpha-1 antitrypsin ...
  • Study Participants

    25
The primary purpose of this study is to characterize the pharmacokinetic profile of intravenous Aralast Fraction (Fr.) IV-1, a sterile, stable, lyophilized preparation of functionally intact human Alpha1- Proteinase Inhibitor (α1-PI). This pharmacokinetic study will be a randomized controlled clinical trial with a cross-over design. Twenty-four subjects will be enrolled into the study. Overall study duration will be approximately 6-8 months.
Study Started
Dec 20
2005
Primary Completion
Jun 05
2006
Study Completion
Jun 05
2006
Results Posted
Jul 20
2011
Estimate
Last Update
May 13
2021

Biological Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor

Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.

Biological Dose of 60 mg/kg alpha1-proteinase inhibitor

Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.

ARALAST Fr. IV-1 Experimental

60 mg/kg

ARALAST Active Comparator

60mg/kg

Criteria

Inclusion Criteria:

The subject or subject´s legally authorized representative has provided written informed consent
Subject is 18 years of age or older
Subject has a documented, endogenous plasma Alpha1-PI level < 8 Micromolar
Subject is of the genotype Pi*Z/Z, Pi*Z/Null, Pi*Null/Null, Pi*Malton/Z, or others, dependent on the approval by the Sponsor
If the subject is female or of childbearing potential, the subject has a negative urine test for pregnancy within 7 days prior to first study product administration and agrees to employ adequate birth control measures for the duration of the study

Laboratory results obtained at the screening visit, meeting the following criteria:

Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) <= 2 times the upper limit of normal (ULN)
Serum total bilirubin <= 2 times ULN
Proteinuria < +2 on dipstick analysis
Serum creatinine <= 1.5 times ULN
Absolute neutrophil count (ANC) >= 1500 cells/mm3
Hemoglobin >= 10.0 g/dL
Platelet count >= 10^5/mm3
If the subject is treated with any respiratory medications, including inhaled bronchodilators and inhaled or oral corticosteroids, the subjects´ medication doses were unchanged for at least 14 days prior to first study product administration
Nonsmoker for a minimum of 3 months prior to first study product administration

Exclusion Criteria:

The subject has received any Alpha1-PI augmentation therapy (including Aralast and investigational Alpha1-PIs, by any route including intravenous and inhaled) within 42 days prior to first study product administration
The subject has received an investigational drug or device within 1 month prior to first study product administration, or the subject is currently receiving an investigational drug
The subject has a known selective immunoglobulin A (IgA) deficiency (IgA level < 15 mg/dL) and/or antibody to IgA
The subject has a pulmonary exacerbation or had a pulmonary exacerbation in the past 14 days prior to first study product administration
The subject is pregnant or lactating, or intends to become pregnant during the course of the study
The subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance

Summary

ARALAST Fr. IV-1

ARALAST

All Events

Event Type Organ System Event Term ARALAST Fr. IV-1 ARALAST

Area Under the Curve/Dose

Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose.

ARALAST Fr. IV-1

0.0822
days*kg/mL (Median)
Full Range: 0.075 to 0.094

ARALAST

0.092
days*kg/mL (Median)
Full Range: 0.0804 to 0.098

Time to Maximum α1-PI Concentration Post-infusion (Tmax)

Time to reach C-max. Tmax is the number of days from infusion to maximum concentration. Samples drawn at the end of infusion are considered to be time zero.

ARALAST Fr. IV-1

ARALAST

Terminal Half-life

Computed from the terminal or disposition rate constant obtained from log_e -linear fitting using the least squares deviation to the last five quantifiable concentrations above pre-infusion level.

ARALAST Fr. IV-1

4.1
days (Median)
Full Range: 3.1 to 5.4

ARALAST

4.2
days (Median)
Full Range: 4.0 to 5.2

Total Area Under the Curve Per Dose

Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose

ARALAST Fr. IV-1

0.0825
days*kg/mL (Median)
Full Range: 0.075 to 0.095

ARALAST

0.0928
days*kg/mL (Median)
Full Range: 0.0812 to 0.099

Systemic Clearance (CL)

Computed as dose divided by AUC 0-infinity (AUC 0-infinity was calculated as the sum of AUC from time 0 to the time of last quantifiable concentration plus a tail area correction)

ARALAST Fr. IV-1

951.0
mL/day (Median)
Full Range: 782.0 to 1115.0

ARALAST

856.0
mL/day (Median)
Full Range: 782.0 to 918.0

Mean Residence Time (MRT)

Computed as total area under the moment curve (AUMC) divided by total AUC

ARALAST Fr. IV-1

6.8
days (Mean)
Standard Deviation: 3.9

ARALAST

6.9
days (Mean)
Standard Deviation: 2.8

Apparent Volume of Distribution at Steady State

Computed as weight-adjusted CL * MRT

ARALAST Fr. IV-1

5606.0
mL (Median)
Full Range: 4624.0 to 6162.0

ARALAST

5405.0
mL (Median)
Full Range: 4454.0 to 6703.0

Incremental Recovery

Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).

ARALAST Fr. IV-1

0.0259
(mg/mL) / (mg/kg) (Median)
Full Range: 0.0234 to 0.028

ARALAST

0.0258
(mg/mL) / (mg/kg) (Median)
Full Range: 0.0237 to 0.027

Maximum Plasma Concentration (Cmax)

Maximum α1-PI concentration following infusion

ARALAST Fr. IV-1

1.7
mg/mL (Median)
Full Range: 1.4 to 1.8

ARALAST

1.7
mg/mL (Median)
Full Range: 1.5 to 1.8

Adverse Events (AEs)

Investigators assessed severity of AEs (occurring during or after infusions) based on: MILD: Transient discomfort, does not interfere in a significant manner with participant's normal functioning level; Resolves spontaneously or may require minimal therapeutic intervention MODERATE: AE produces limited impairment of function, can require therapeutic intervention; AE produces no sequelae; SEVERE: AE results in marked impairment of function, can lead to temporary inability to resume usual life pattern; AE produces sequelae, which require prolonged therapeutic intervention

ARALAST Fr. IV-1

Non-Serious AEs - Mild

43.0
Events

Non-Serious AEs - Moderate

16.0
Events

Non-Serious AEs - Severe

2.0
Events

Serious AEs

ARALAST

Non-Serious AEs - Mild

45.0
Events

Non-Serious AEs - Moderate

12.0
Events

Non-Serious AEs - Severe

3.0
Events

Serious AEs

Age, Continuous

59
years (Median)
Full Range: 20.0 to 75.0

Region of Enrollment

Sex: Female, Male

Period 1

ARALAST Fr. IV-1 Then Aralast

ARALAST Then ARALAST Fr. IV-1

Period 2

ARALAST Fr. IV-1 Then Aralast

ARALAST Then ARALAST Fr. IV-1