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Trasylol (Aprotinin) - Description and Clinical Pharmacology

 
 



TRASYLOL®
(aprotinin injection)

DESCRIPTION

Trasylol® (aprotinin injection), C284H432N84O79S7, is a natural proteinase inhibitor obtained from bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid residues that are arranged in a single polypeptide chain, cross-linked by three disulfide bridges. It is supplied as a clear, colorless, sterile isotonic solution for intravenous administration. Each milliliter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.

Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).

The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.

Pharmacokinetics:

The studies comparing the pharmacokinetics of aprotinin in healthy volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU to 2 million KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration. Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.

Average steady state intraoperative plasma concentrations were 137 KIU/mL (n=10) after administration of the following dosage regimen: 1 million KIU IV loading dose, 1 million KIU into the pump prime volume, 250,000 KIU per hour of operation as continuous intravenous infusion (Regimen B). Average steady state intraoperative plasma concentrations were 250 KIU/mL in patients (n=20) treated with aprotinin during cardiac surgery by administration of Regimen A (exactly double Regimen B): 2 million KIU IV loading dose, 2 million KIU into the pump prime volume, 500,000 KIU per hour of operation as continuous intravenous infusion.

Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Animal studies have shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes. Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.

CLINICAL TRIALS

Repeat Coronary Artery Bypass Graft Patients:

Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of 540 randomized patients undergoing repeat coronary artery bypass graft (CABG) surgery, 480 were valid for efficacy analysis. The following treatment regimens were used in the studies:

Trasylol® Regimen A (2 million KIU IV loading dose, 2 million KIU into the pump prime volume, and 500,000 KIU per hour of surgery as a continuous intravenous infusion); Trasylol® Regimen B (1 million KIU IV loading dose, 1 million KIU into the pump prime volume, and 250,000 KIU per hour of surgery as a continuous intravenous infusion); a pump prime regimen (2 million KIU into the pump prime volume only); and a placebo regimen (normal saline). All patients valid for efficacy in the above studies were pooled by treatment regimen for analyses of efficacy.

In this pooled analysis, fewer patients receiving Trasylol®, either Regimen A or Regimen B, required any donor blood compared to the pump prime only or placebo regimens. The number of units of donor blood required by patients, the volume (milliliters) of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and the total thoracic drainage volumes were also reduced in patients receiving Trasylol® as compared to placebo.

Efficacy Variables: Repeat CABG Patients Mean (S.D.) or % of Patients
† The pump prime regimen was evaluated in only one study in patients undergoing repeat CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05 (Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety are not statistically significant.
a Excludes patients who required reoperation
VARIABLE
PLACEBO
REGIMEN
N=156
Trasylol®
PUMP PRIME
REGIMEN†
N=68
Trasylol®
REGIMEN
B**
N=113
Trasylol®
REGIMEN
A**
N=143
% OF REPEAT CABG
PATIENTS WHO
REQUIRED
DONOR BLOOD
76.3%72.1%48.7%46.9%
 
UNITS OF
DONOR BLOOD
TRANSFUSED
3.7 (4.4)2.5 (2.4)2.2 (5.0)*1.6 (2.9)*
 
mL OF
DONOR BLOOD
TRANSFUSED
1132 (1443)756 (807)723 (1779)*515 (999)*
 
PLATELETS
TRANSFUSED (Donor Units)
5.0 (10.0)2.1 (4.6)*1.3 (4.6)*0.9 (4.3)*
 
CRYOPRECIPITATE
TRANSFUSED (Donor Units)
0.9 (3.5)0.0 (0.0)*0.5 (4.0)0.1 (0.8)*
 
FRESH FROZEN
PLASMA TRANSFUSED
(Donor Units)
1.3 (2.5)0.5 (1.4)*0.3 (1.1)*0.2 (0.9)*
 
THORACIC DRAINAGE
RATE (mL/hr)
89 (77)73 (69)66 (244)40 (36)*
 
TOTAL THORACIC
DRAINAGE VOLUME (mL)a
1659 (1226) 1561 (1370)1103 (2001)*960 (849)*
 
REOPERATION FOR
DIFFUSE BLEEDING
1.9%2.9%0%0%

Primary Coronary Artery Bypass Graft Patients:

Four placebo-controlled, double-blind studies of Trasylol® were conducted in the United States; of 1745 randomized patients undergoing primary CABG surgery, 1599 were valid for efficacy analysis. The dosage regimens used in these studies were identical to those used in the repeat CABG studies described above (Regimens A, B, pump prime, and placebo). All patients valid for efficacy were pooled by treatment regimen.

In this pooled analysis, fewer patients receiving Trasylol® Regimens A, B, and pump prime required any donor blood in comparison to the placebo regimen. The number of units of donor blood required by patients, the volume of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and total thoracic drainage volumes were also reduced in patients receiving Trasylol® as compared to placebo.

Efficacy Variables: Primary CABG Patients Mean (S.D.) or % of Patients
† The pump prime regimen was evaluated in only one study in patients undergoing primary CABG surgery. Note: The pump prime only regimen is not an approved dosage regimen.
* Significantly different from placebo, p<0.05 (Transfusion variables analyzed via ANOVA on ranks)
** Differences between Regimen A (high dose) and Regimen B (low dose) in efficacy and safety are not statistically significant.
VARIABLE
PLACEBO
REGIMEN
N=624
Trasylol®
PUMP PRIME
REGIMEN†
N=159
Trasylol®
REGIMEN
B**
N=175
Trasylol®
REGIMEN
A**
N=641
 
% OF PRIMARY CABG
PATIENTS WHO
REQUIRED
DONOR BLOOD
53.5% 32.7%*37.1%*36.8%*
 
 
UNITS OF
DONOR BLOOD
TRANSFUSED
1.7 (2.4)0.9 (1.6)*1.0 (1.6)*0.9 (1.4)*
 
mL OF
DONOR BLOOD
TRANSFUSED
584 (840)286 (518)*313 (505)*295 (503)*
 
PLATELETS
TRANSFUSED (Donor Units)
1.3 (3.7)0.5 (2.4)*0.3 (1.6)*0.3 (1.5)*
 
CRYOPRECIPITATE
TRANSFUSED (Donor Units)
0.5 (2.2)0.0 (0.0)*0.1 (0.8)*0.0 (0.0)*
 
FRESH FROZEN
PLASMA TRANSFUSED
(Donor Units)
0.6 (1.7)0.2 (1.7)*0.2 (0.8)*0.2 (0.9)*
 
THORACIC DRAINAGE
RATE (mL/hr)
87 (67)51 (36)*45 (31)*39 (32)*
 
TOTAL THORACIC
DRAINAGE VOLUME (mL)
1232 (711)852 (653)*792 (465)*705 (493)*
 
REOPERATION FOR
DIFFUSE BLEEDING
1.4%0.6%0% 0%*

Additional subgroup analyses showed no diminution in benefit with increasing age. Male and female patients benefited from Trasylol® with a reduction in the average number of units of donor blood transfused. Although male patients did better than female patients in terms of the percentage of patients who required any donor blood transfusions, the number of female patients studied was small.

A double-blind, randomized, Canadian study compared Trasylol® Regimen A (n=28) and placebo (n=23) in primary cardiac surgery patients (mainly CABG) requiring cardiopulmonary bypass who were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs. 2532.3 mL) and the mean number of units of packed red blood cells transfused (1.6 units vs 4.3 units) were significantly less (p<0.008) in the Trasylol® group compared to the placebo group.

In a U.S. randomized study of Trasylol® Regimen A and Regimen B versus the placebo regimen in 212 patients undergoing primary aortic and/or mitral valve replacement or repair, no benefit was found for Trasylol® in terms of the need for transfusion or the number of units of blood required.

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