Iprivask (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Desirudin is a direct inhibitor of free circulating and clot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human plasma. One molecule of desirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected. Activated partial thromboplastin time (aPTT) is a measure of the anticoagulant activity of desirudin and increases in a dose-dependent fashion.

12.2 Pharmacodynamics

The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Iprivask therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.

12.3 Pharmacokinetics

Properties

Pharmacokinetic parameters were calculated based on plasma concentration data obtained by a non-specific ELISA method that does not discriminate between native desirudin and its metabolites. It is not known if the metabolites are pharmacologically active.

Absorption

The absorption of desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of desirudin increased to a maximum level (C max ) between 1 and 3 hours. Both C max and area-under-the-curve (AUC) values are dose proportional.

Mean Desirudin Concentrations and Changes in APTT

After A Single 15 mg Subcutaneous Dose in 12 Healthy Subjects

Description: graph
(click image for full-size original)

Distribution

The pharmacokinetic properties of desirudin following intravenous administration are well described by a two-or three-compartment disposition model. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin, forming an extremely tight, non-covalent complex with an inhibition constant of approximately 2.6 x 10 -13 M. Thus, free or protein bound desirudin immediately binds circulating thrombin. The pharmacological effect of desirudin is not modified when co-administered with highly protein bound drugs (>99%).

Metabolism

Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (< 7%). There is no evidence for the presence of other metabolites. This indicates that desirudin is metabolized by stepwise degradation from the C-terminus probably catalyzed by carboxypeptidase(s) such as carboxypeptidase A, originating from the pancreas. Total clearance of desirudin is approximately 1.5 to 2.7 mL/min/kg following either subcutaneous or intravenous administration and is independent of dose. This clearance value is close to the glomerular filtration rate.

Elimination

The elimination of desirudin from plasma is rapid after intravenous administration, with approximately 90% of the dose disappearing from the plasma within 2 hours of the injection. Plasma concentrations of desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.

Specific Populations

Renal Impairment

In a pharmacokinetic study of renally impaired subjects, subjects with mild [creatinine clearance (CLcr) between 61 and 90 mL/min], moderate (CLcr between 31 and 60 mL/min), and severe (CLcr below 31 mL/min) renal impairment, were administered a single intravenous dose of 0.5, 0.25, or 0.125 mg/kg desirudin, respectively. This resulted in mean dose-normalized AUC effect (AUC 0-60th for aPTT prolongation) increases of approximately 3-, and 9-fold for the moderate and severe renally impaired subjects, respectively, compared with healthy individuals. In subjects with mild renal impairment, there was no increase in AUC effect compared with healthy individuals. In subjects with severe renal impairment, terminal elimination half-lives were prolonged up to 12 hours compared with 2 to 4 hours in normal volunteers or subjects with mild to moderate renal impairment. Dose adjustments are recommended in certain circumstances in relation to the degree of impairment or degree of aPTT abnormality [ see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.5) ] .

Hepatic Impairment

No pharmacokinetic studies have been conducted to investigate the effects of Iprivask in hepatic impairment.

Age and Gender

The mean plasma clearance of desirudin in patients ≥65 years of age (n=12; 110 mL/min) is approximately 28% lower than in patients <65 years of age (n=8; 153 mL/min). Population pharmacokinetics conducted in 301 patients undergoing elective total hip replacement indicate that age or gender do not affect the systemic clearance of desirudin when renal creatinine clearance is considered. This drug is substantially excreted by the kidney, and the risk of adverse events due to it may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of moderate and severe renal impairment is necessary. [ see Dosage and Administration (2.2) ] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been conducted to evaluate the carcinogenic potential of desirudin.

Desirudin was not genotoxic in the Ames test, the Chinese hamster lung cell (V79/HGPRT) forward mutation test or the rat micronucleus test. It was, however, equivocal in its genotoxic effect in Chinese hamster ovarian cell (CCL 61) chromosome aberration tests.

Desirudin at subcutaneous doses up to 10mg/kg/day (about 2.7 times the recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Iprivask was evaluated in two controlled, randomized, multicenter, clinical efficacy trials and a controlled, double-blind, dose-finding study. In the efficacy studies, Iprivask was compared to subcutaneously administered unfractionated heparin or enoxaparin sodium for the reduction of the risk of venous thromboembolic events (VTE) in patients undergoing total hip replacement surgery. In all studies Iprivask was initiated prior to surgery and continued for 8 to 12 days postoperatively (median duration 10 days).

In the first study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5000 IU subcutaneously administered every 8 hours. A total of 445 patients were randomized in the study, 436 patients were treated, and 85 of the treated patients were excluded from efficacy analysis, mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 34 to 89 years (mean age 68.4 years) with 41.8% men and 58.2% women. All enrolled patients were Caucasian. Iprivask significantly reduced the number of total VTE compared to unfractionated heparin: Evaluable population: Iprivask, 13/174 (7.5%) vs. heparin, 41/177 (23.2%); p value <0.001; Intent-to-Treat population: Iprivask 13/225 (5.8%) vs. heparin 42/220 (19.1%); p value <0.0001]. Significantly fewer patients in the group treated with Iprivask experienced proximal DVT than those patients treated with heparin: Evaluable population: Iprivask 6/174 (3.4%) vs. heparin 29/177 (16.4%); p value <0.001: Intent-to-Treat population: Iprivask 6/225 (2.7%) vs. heparin 30/220 (13.6%); p value <0.0001.

In a second study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to enoxaparin sodium 40 mg subcutaneously administered every 24 hours. A total of 2079 patients were randomized in the study, 2049 patients were treated, and 508 of the treated patients were excluded from efficacy analysis mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 18 to 90 years (mean age 68.5 years) with 41.7% men and 58.5% women. All enrolled patients were Caucasian. In both the evaluable patient population and the intent-to-treat population, patients who received Iprivask had a lower incidence of major VTE, total VTE, and proximal DVT than did patients who received enoxaparin (see table below).

Efficacy of Iprivask in Hip Replacement Surgery Patients

Dosing Regimen

Iprivask a 15 mg q12h SC

Enoxaparin a 40 mg qd

Evaluable Hip Replacement Surgery Patients

n=773

n=768

n (%)

n (%)

p Value

Treatment FailuresMajor VTE b,c

39 (4. 9) d

61 (7.9)

p<0.02

Total VTE e

145 (18.8)

197 (25.7)

p<0.001

Proximal DVT

36 (4.5)

59 (7.7)

p=0.012

Intent-to-Treat Hip Replacement Surgery Patients

n=1043

n=1036

n (%)

n (%)

p Value

Treatment Failures

Major VTE b

39 (3.7) f

61 (5.9)

p=0.024

Total VTE e

145 (13.9)

199 (19.2)

p=0.001

Proximal DVT

36 (3.5)

59 (5.7)

p=0.012

a Treatment was initiated no more than 30 minutes preoperatively, but after induction of regional block anesthesia, if used.
b Major VTE included proximal DVT, PE, or death.
c Total number of patients in this evaluation: Iprivask 802; Enoxaparin 785.
d Odds ratio 0.61 with 95% Confidence Interval of: 0.40; 0.92
e Total VTE = Venous thromboembolic events which included DVT (including proximal events), PE, or death considered to be thromboembolic in origin.
f Odds ratio 0.62 with 95% Confidence Interval of 0.41; 0.94

In a multicenter, double-blind, dose-finding study, Iprivask 10 mg, 15 mg, and 20 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5,000 IU administered every 8 hours subcutaneously in patients undergoing hip replacement surgery. A dose response was seen with regard to both effectiveness and bleeding complications. The 15-mg and 20-mg doses were superior to heparin and the 10-mg dose. In a smaller, open-labeled, dose-finding study of Iprivask 10 mg, 15 mg, 20 mg, and 40 mg subcutaneously administered every 12 hours in patients undergoing hip replacement surgery, the 40-mg dose was associated with unacceptable major bleeding.

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