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Atryn

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Atryn

CLINICAL PHARMACOLOGY

Mechanism of Action

Antithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and Factor Xa5, the serine proteases that play pivotal roles in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.

Pharmacodynamics

Hereditary AT deficiency causes an increased risk of venous thromboembolism (VTE). During high-risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 506,7.

In hereditary antithrombin deficient patients ATryn (recombinant lyophilized powder) restores (normalize) plasma AT activity levels during peri-operative and peri-partum periods.

Pharmacokinetics

In an open-label, single dose pharmacokinetic study, male and female patients ( ≥ 18 years of age) with hereditary AT deficiency, received either 50 (n = 9, all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn (recombinant lyophilized powder) intravenously. These patients were not in high-risk situations. The baseline corrected pharmacokinetic parameters for antithrombin (Recombinant) are summarized in Table 5.

Table 5: Baseline Corrected Mean Pharmacokinetic Parameters (%CV)

Parameter 50 IU/kg 100 IU/kg
CL (mL/hr/kg) 9.6 (34.4) 7.2 (15.3)
Half-life (hrs) 11.6 (84.7) 17.7 (60.9)
MRT (hrs) 16.2 (74.9) 20.5 (40.2)
Vss (mL/kg) 126.2 (37.4) 156.1 (43.4)

Incremental recovery [mean (%CV)] was 2.24 (20.2) and 1.94 (14.8) %/IU/kg body weight for 50 and 100 IU/kg, respectively.

Population pharmacokinetic analysis of hereditary deficient patients in a high risk situation revealed that the clearance and volume of distribution in pregnant patients were (1.38 L/h and 14.3 L respectively) which are higher than non-pregnant patients (0.67 L/h and 7.7 L respectively). Therefore, distinct dosing formulae for surgical and pregnant patients should be used (see Recommended Dose and Schedule).

As compared to plasma derived antithrombin, ATryn (recombinant lyophilized powder) has a shorter half-life and more rapid clearance (approximately nine and seven times, respectively).

Pharmacokinetics may be influenced by concomitant heparin administration, as well as surgical procedures, delivery, or bleeding. AT activity monitoring (see Recommended Dose and Schedule) should be performed to properly treat such patients.

Animal Toxicology and/or Pharmacology

Pharmacokinetic and toxicokinetic (1 single, 2 repeated dose) studies of antithrombin (Recombinant) were performed in mice, rats, dogs and monkeys. In toxicokinetic studies in monkeys the area under the curve was 3-4 times greater than in the rat at all doses used.

The toxicological profile of antithrombin (Recombinant) administered by the intravenous route as bolus injections and infusions has been evaluated in both single- and repeat-dose studies performed in rats, dogs, and monkeys across a range of doses from 2.1 to 360 mg/kg. The highest doses in the single dose toxicity studies in rats and dogs were 360 mg/kg and 210 mg/kg, respectively. Toxicities observed were limited to transient injection site swelling observed in rats and dogs at the highest doses tested, and increased AST at highest dose in the dog study, both resolved during recovery period.

The highest dose in the 28-day repeated-dose toxicity study in rats was 360 mg/kg/day. The toxicity at this dose was limited to transient limb swelling and local injection site bruising and swelling. The highest dose in the 14-day repeated-dose toxicity study in monkeys was 300 mg/kg/day or approximately 7-8 times human dose. Toxicities observed in female monkeys at this dose included internal bleeding, hematological changes and liver toxicity, with one out of three female animals showing multifocal hepatic necrosis. Both sexes showed increased AST and ALK on day 15, with both parameters returning to normal by day 22. There was no adverse effect in monkeys dosed with 120 mg/kg/day.

Clinical Studies

The efficacy of ATryn (recombinant lyophilized powder) to prevent the occurrence of venous thromboembolic events was assessed by comparing the incidence of the occurrence of such events in 31 ATryn (recombinant lyophilized powder) treated hereditary AT deficient patients with the incidence in 35 human plasma-derived AT treated hereditary AT deficient patients. Data on ATryn (recombinant lyophilized powder) -treated patients were derived from two prospective, single-arm, open-label studies. Data on plasma AT treated patients were collected from a prospectively designed concurrently conducted retrospective chart review. Patients in both studies had confirmed hereditary AT deficiency (AT activity ≤ 60% of normal) and a personal history of thromboembolic events. Patients had to be treated in the peri-operative and peri-partum period. ATryn (recombinant lyophilized powder) was administered as a continuous infusion for at least 3 days, starting one day prior to the surgery or delivery. Plasma AT was administered for at least two days as single bolus infusions. Due to the retrospective nature of the study, dosing was done with the locally available AT concentrate according to the local practice.

The occurrence of a venous thromboembolic event was confirmed if signs and symptoms for such events were confirmed by a specific diagnostic assessment, or when treatment for an event was initiated based on diagnostic imaging, without the presence of signs and symptoms. The efficacy was assessed during treatment with AT and up to 7 days after stopping AT treatment.

In the ATryn (recombinant lyophilized powder) -treated group there was one confirmed diagnosis of an acute deep vein thrombosis (DVT). The incidence of any thromboembolic event from the start of treatment to 7 days after last dosing is summarized by treatment group in Table 6 as are the Clopper-Pearson exact 95% CI for the proportion of patients with a thromboembolic event and the exact 95% lower confidence bound for the difference between treatments.

Table 6: Overall Incidence of Any Confirmed Thromboembolic Event

Plasma AT ATryn Lower
95%
Confidence
Bound of
Difference
No. of Pts. Assessed No. of Pts. with Events % of Pts. with Events 95% CI* No. of Pts. Assessed No. of Pts. with Events % of Pts. with Events 95% CI
35 0 0.0 0.00, 10.00 31 1 3.2 0.08, 16.70 -0.167
* The 95% confidence intervals were calculated using Clopper-Pearson methodology. AT=Antithrombin; No.=Number; Pts.=Patients; CI=Confidence Interval

The lower 95% confidence bound of difference between treatment groups was -0.167, a value that is greater than the pre-specified lower confidence bound of -0.20. This demonstrates that ATryn (recombinant lyophilized powder) was non-inferior to plasma AT in terms of the prevention of peri-operative or peri-partum thromboembolic events.

Supportive data come from a study in the same population with 5 hereditary AT deficient patients treated on 6 occasions in a compassionate use program and provides additional reassurance of the efficacy of ATryn (recombinant lyophilized powder) . None of these patients reported a thromboembolic event.2

REFERENCES

(2) Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion 2003 March;43(3):390-4.

(5) Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40.

(6) Buchanan GS, Rodgers GM, Ware Branch. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003 June;17(3):397-411.

(7) Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.

Last reviewed on RxList: 3/10/2009
This monograph has been modified to include the generic and brand name in many instances.

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