Human plasma protein fraction

Human plasma protein fraction is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis.

The total protein concentration is 45-70 mg/mL. The protein distribution is within the normal range of human plasma, please refer to table below. Protein S and Plasmin inhibitor levels have been found to be below the range for normal human plasma. The final product release limits are ≤0.3 IU/ml and ≤2.0 U/ml, respectively.

After S/D treatment and subsequent removal of S/D reagents, the plasma protein content and distribution in human plasma protein fraction remain at comparable levels to those in normal fresh frozen plasma.

Plasma Protein Levels in Human Plasma Protein Fraction Compared to Single-Donor Fresh-Frozen Plasma:

12 consecutive batches human plasma protein fraction were investigated; mean (minimum-maximum) values are presented; FFP, single-donor fresh-frozen plasma

One clinical study aimed to investigate the pharmacodynamics of human plasma protein fraction has been performed.

Five male and six female patients, included for hereditary, acquired, isolated or combined coagulation deficiency, received lyophilised human plasma protein fraction as a single, i.v. injection. Thereof, 2 patients each had a factor VII or factor X, and 4 patients a factor XI deficiency. Two patients received human plasma protein fraction lyophylisate for ongoing bleeding, one for plasmapheresis and eight for prevention of bleeding before an invasive procedure. Bleeding was stopped in the two patients with ongoing bleeding. In the nine other patients, plasmapheresis and surgical procedures were uneventful, with no abnormal bleeding. The overall effectiveness of human plasma protein fraction as rated by the investigator was good in all patients.

Two patients experienced a total of three adverse events (AEs), consisting of an anaphylactoid reaction and urticaria with pruritus. These AEs resolved with an antihistaminic and both patients recovered. No patient dropped out of the study for safety reasons. No serious and/or unexpected AEs occurred. No adverse laboratory findings were observed for haematology, blood biochemistry and viral safety parameters.

During one clinical study pharmacokinetic data of coagulation factors after treatment with human plasma protein fraction reconstituted as lyophylisate have been collected from eight patients suffering from hereditary coagulation factor deficiencies. All patients received a single human plasma protein fraction infusion of an average of 580 mL (range 400 to 1,600 mL). The dose administered was expected to achieve and maintain a plasma concentration of 10% to 20% of normal of the deficient coagulation factor. The pharmacokinetic results are shown in the table below.

Pharmacokinetic results:

Vd volume of distribution; CL clearance; MRT mean residence time; T½ half life; IU international unit.

These pharmacokinetics parameters after human plasma protein fraction administration were within the kinetic profile of coagulation factors after administration of FFP. No pharmacokinetic results are available for the remaining coagulation factors.

Absorption

Human plasma protein fraction is administered intravenously and therefore immediately available in the organism.

Distribution, Metabolism and Excretion

Human plasma protein fraction is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis. Human plasma may cause severe toxic reactions in animals and is not tolerated at dosages approaching those generally used in humans. Routine pharmacology testing in laboratory animals is not considered to add any relevant information for the safety and efficacy of human plasma protein fraction in the clinical use.

Two contaminants derived from the manufacturing process, namely Tri(n-butyl)phosphate (TNBP) and Octoxynol, might be present in the final product (see DETAILED PHARMACOLOGY – Animal Pharmacology and TOXICOLOGY). A program of studies has been carried out to assess the pharmacokinetic profile of TNBP and Octoxynol. After i.v. administration in rats, TNBP disappeared rapidly from the plasma with an elimination half-life of approximately 20 min. TNBP was not found at any time in the urine and only very small amounts were detectable in the faeces. Concomitantly administered Octoxynol could not be detected in the plasma, the urine or the faeces.

Special Populations and Conditions

No specific pharmacokinetic studies have been performed in patients at increased risk, such as elderly subjects or patients with renal or hepatic impairment.

Animal Pharmacology

Human plasma protein fraction is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis. Human plasma may cause severe toxic reactions in animals and is not tolerated at dosages approaching those generally used in humans. Routine pharmacology testing in laboratory animals is not considered to add any relevant information for the safety and efficacy of human plasma protein fraction in the clinical use.

The level of impurities putatively present in the end product is controlled by the manufacturing process itself, specifications for the raw materials and in process controls, as well as by the final product specification. Two contaminants derived from the manufacturing process, namely TNBP and Octoxynol, may be present in the final product at levels not exceeding 2.0 mcg/mL for TNBP and 5.0 mcg/mL for Octoxynol. A program of studies has been carried out to assess the pharmacokinetic profile of TNBP and Octoxynol. It should be borne in mind that the exposure to TNBP and Octoxynol may be large in patients undergoing therapeutic plasmapheresis. After i.v. administration in rats, TNBP disappeared rapidly from the plasma with an elimination half-life of approximately 20 min. TNBP was not found at any time in the urine and only very small amounts were detectable in the faeces. Concomitantly administered Octoxynol could not be detected in the plasma, the urine or the faeces.

Animal Pharmacokinetics and Metabolism

A pharmacokinetic study was carried out by the applicant in rats, which were given 300 mcg of TNBP/kg + 1,500 mcg of Octoxynol/kg BM i.v. The plasma half-life for TNBP was approximately 20 minutes, Octoxynol was not detected.

According to published data ²⁵ the plasma half-life for TNBP in rats after intravenous administration of 5 mg/kg is 1.3 hours. The main excretion route is via the urine, small amounts are excreted via faeces and the breathing air (CO₂).

There are no pharmacokinetic studies for Octoxynol in the literature. However, the very similar nonoxynol-9 is excreted (within 7 days) via the faeces 52-78%, the urine 20-39% and the breathing air (CO₂) 0-1.2% in rats after oral and intraperitoneal administration.