A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Innohep Pharmacology, Pharmacokinetics, Studies, Metabolism - Tinzaparin
Innohep Pharmacology, Pharmacokinetics, Studies, Metabolism - Tinzaparin
CLINICAL PHARMACOLOGY
Tinzaparin sodium is a low molecular weight heparin with antithrombotic properties.
Tinzaparin sodium inhibits reactions that lead to the clotting of blood including
the formation of fibrin clots, both in vitro and in vivo . It
acts as a potent co-inhibitor of several activated coagulation factors, especially
Factors Xa and IIa (thrombin). The primary inhibitory activity is mediated through
the plasma protease inhibitor, antithrombin.
Bleeding time is usually unaffected by tinzaparin sodium. Activated partial
thromboplastin time (aPTT) is prolonged by therapeutic doses of tinzaparin sodium
used in the treatment of deep vein thrombosis (DVT). Prothrombin time (PT) may
be slightly prolonged with tinzaparin sodium treatment but usually remains within
the normal range. Neither aPTT nor PT can be used for therapeutic monitoring
of tinzaparin sodium.
Neither unfractionated heparin nor tinzaparin sodium have intrinsic fibrinolytic
activity; therefore, they do not lyse existing clots. Tinzaparin sodium induces
release of tissue factor pathway inhibitor, which may contribute to the antithrombotic
effect. Heparin is also known to have a variety of actions that are independent
of its anticoagulant effects. These include interactions with endothelial cell
growth factors, inhibition of smooth muscle cell proliferation, activation of
lipoprotein lipase, suppression of aldosterone secretion, and induction of platelet
aggregation.
Pharmacokinetics/Pharmacodynamics
Anti-Xa and anti-IIa activities are the primary biomarkers for assessing tinzaparin
sodium exposure because plasma concentrations of low molecular weight heparins
cannot be measured directly. Because of analytical assay limitations, anti-Xa
activity is the more widely used biomarker. The measurements of anti-Xa and
anti-IIa activities in plasma serve as surrogates for the concentrations of
molecules which contain the high-affinity binding site for antithrombin (anti-Xa
and anti-IIa activities). Monitoring patients based on anti-Xa activity is generally
not advised. The data is provided in Table 2 below.
Studies with tinzaparin sodium in healthy volunteers and patients have been
conducted with both fixed- and weight-adjusted dose administration. Recommended
therapy with tinzaparin sodium is based on weight-adjusted dosing (see DOSAGE
AND ADMINISTRATION ).
Table 2
Summary of Pharmacokinetic Parameters (Mean and Standard Deviation)
Based on Anti-Xa Activity Following a Single SC Administration of
Tinzaparin Sodium to Healthy Volunteers
|
Parameter
|
Single Dose |
Multiple Dose Dose |
| |
4,500 IU * |
Day 1 175 IU/kg |
Day 5 175 IU/kg |
|
C max (IU/mL)
|
0.25 (0.05) |
0.87 (0.15) |
0.93 (0.15) |
|
T max (hr)
|
3.7 (0.9) |
4.4 (0.7) |
4.6 (1.0) |
|
AUC 0-(infinity) (IU * hr/mL)
|
2.0 (0.5) |
9.0 (1.1) |
9.7 (1.4) |
|
Half-life (hr)
|
3.4 (1.7) |
3.3 (0.8) |
3.5 (0.6) |
| * Dosing based on fixed dose of 4,500 IU. Mean dose
administered was 64.3 IU/kg. |
Absorption
Plasma levels of anti-Xa activity increase in the first 2 to 3 hours following SC injection of
tinzaparin sodium and reach a maximum within 4 to 5 hours. Maximum concentrations (Cmax)
of 0.25 and 0.87 IU/mL are achieved following a single SC fixed dose of 4,500 IU (approximately
64.3 IU/kg) and weight-adjusted dose of 175 IU/kg of tinzaparin sodium, respectively. Based
on the extent of absorption (AUC0-¥), a comparison of 4,500 IU and 12,250 IU single doses
indicates that increases in anti-Xa activity are greater than dose proportional relative to the
increase in dose. Following a single SC injection of tinzaparin sodium, the mean anti-Xa to anti-
IIa activity ratio, based on the area under the anti-Xa and anti-IIa time profiles, is 2.8 and is
higher than that of unfractionated heparin (approximately 1.2). The absolute bioavailability
(following 4,500 IU SC and intravenous [IV] administrations) is 86.7% based on anti-Xa activity.
Distribution
The volume of distribution of tinzaparin sodium ranges from 3.1 L to 5.0 L. These values are
similar in magnitude to blood volume, suggesting that the distribution of anti-Xa activity is limited
to the central compartment.
Metabolism
Low molecular weight heparins are partially metabolized by desulphation and depolymerization.
Elimination
In healthy volunteers, the elimination half-life following SC administration of 4,500 IU or 175
IU/kg tinzaparin sodium is approximately 3-4 hours based on anti-Xa activity. Clearance following
IV administration of 4,500 IU tinzaparin sodium is approximately 1.7 L/hr. The primary route
of elimination is renal. Anti-Xa activity did not accumulate with once daily dosing of 175 IU/kg
for five days in healthy volunteers. (See Figure 1 and Table 2.)
Special Populations
Population Pharmacokinetics
Anti-Xa concentrations from approximately 180 patients receiving SC tinzaparin
sodium once daily (175 IU/kg body weight) as the treatment of proximal DVT and
approximately 240 patients undergoing elective hip replacement surgery receiving
SC tinzaparin sodium once daily (~65 IU/kg body weight) were analyzed by population
pharmacokinetic methods. The results indicate that neither age nor gender significantly
alter tinzaparin sodium clearance based on anti-Xa activity (see PRECAUTIONS
, General ). However, a reduction in tinzaparin sodium clearance
was observed in patients with impaired renal function (reduced calculated creatinine
clearance). Weight is also an important factor for the prediction of tinzaparin
sodium clearance, consistent with the recommendation that INNOHEP therapy be
based on weight-adjusted dosing (see DOSAGE AND ADMINISTRATION ).
Renal Impairment
Clinical Studies
In patients being treated with tinzaparin sodium (175 IU/kg) for DVT, a population pharmacokinetic
(PK) analysis determined that tinzaparin sodium clearance based on anti-Xa activity was related
to creatinine clearance calculated by the Cockroft Gault equation. In this PK analysis, a reduction
in tinzaparin sodium clearance in moderate (30-50 mL/min) and severe ( < 30 mL/min) renal
impairment was observed. Patients with severe renal impairment exhibited a 24% reduction in
tinzaparin sodium clearance relative to patients with normal renal function (>80 mL/min).
Hemodialysis Studies
In a study of 12 chronic renal failure patients undergoing hemodialysis, anti-Xa clearance was
reduced 28%, consistent with estimates from the population PK analyses. In another study of
6 patients undergoing hemodialysis, the half-life of anti-Xa activity following a single IV dose of
75 IU/kg of tinzaparin sodium on an off-dialysis day was prolonged relative to that for healthy
volunteers (5.2 versus 1.6 hours).
Patients with severe renal impairment should be dosed with caution (see PRECAUTIONS).
Hepatic Impairment
No prospective studies have assessed tinzaparin sodium pharmacokinetics or
pharmacodynamics in hepatically-impaired patients. However, the hepatic route
is not a major route of elimination of low molecular weight heparins (see WARNINGS
, Hemorrhage ).
Elderly
Since renal function declines with age, elimination of tinzaparin sodium may be reduced in
elderly patients. Tinzaparin sodium is generally safe when administered at a treatment dose
(175 IU/kg) in older patients with age-related renal impairment. In a prospective study of 30
elderly patients [6 men, 24 women; aged 87.0 ± 5.9 years; mean body weight 62.7 ± 14.6 kg;
creatinine clearance 40.6 ± 15.3 mL/min (range 20-72)] treated with tinzaparin sodium 175
IU/kg once daily for ten days for acute venous thromboembolism, there was no accumulation
of anti-Xa activity based on peak anti-Xa activity levels.
Obesity
Based on the results of a prospective clinical study and the population PK analyses, weightbased
dosing is appropriate for heavy/obese patients. Tinzaparin sodium PK parameters based
on anti-Xa activity are independent of body weight and body mass index (BMI) when tinzaparin
sodium is dosed on a weight basis at 175 IU/kg or 75 IU/kg. In a prospective study of heavy/obese
subjects (101 to 165 kg; BMI 26-61 kg/m2), anti-Xa activity time profiles were similar to those in
normal-weight volunteer studies. Data at the 175 IU/kg dose are shown in Figure 2. Clinical trial
experience is limited in patients with a BMI >40 kg/m2.
CLINICAL STUDIES
Treatment of Acute Deep Vein Thrombosis (DVT) With or Without Pulmonary Embolism
(PE)
In a randomized, multicenter, double-blind trial INNOHEP (tinzaparin sodium injection) was
compared to unfractionated heparin in 435 hospitalized patients with symptomatic, proximal DVT.
Six percent of the enrolled patients had symptomatic pulmonary embolism confirmed by segmental
or greater lung scan defect. The study patients ranged in age from 19 to 92 years (mean 61 ±
17 years), 55% were male, 88% were white and 8% black. Patients received either INNOHEP
SC once daily according to body weight (175 IU/kg) and a placebo IV bolus followed by continuous
placebo IV infusion, or unfractionated heparin as an initial IV bolus dose (5,000 IU) followed by
continuous IV infusion of unfractionated heparin with the rate adjusted according to the aPTT
(1.5 to 2.5 times control value) and a once daily SC placebo injection. Treatment continued for
approximately 6 days, and both treatment groups also received oral warfarin sodium starting on
Day 2 which continued to Day 90 with doses titrated to a target INR of 2.0 to 3.0.
The 90-day cumulative thromboembolic (TE) rate [recurrent DVT or PE] with INNOHEP was
not significantly different than the rate with unfractionated heparin. The data are provided in
Table 3.
Table 3
Efficacy of Once Daily INNOHEP in the Treatment of Acute Deep Vein
Thrombosis
| |
Dosing Regimen |
|
Indication
|
INNOHEP 1
175 IU/kg
Once Daily
SC
n (%) |
Heparin 1
5,000 IU Bolus
then aPTT Adjusted
Continuous
Infusion
IV
n (%) |
|
Treatment of Acute DVT
|
|
Intent to Treat Population 2
|
216 (100%) |
219 (100%) |
|
Patient Outcome at 90 Days
|
|
|
|
Total TE 3 Events
|
6 (2.8%) 4 |
15 (6.8%) 4 |
|
DVTs
|
3 (1.4%) |
9 (4.1%) |
|
PEs
|
3 (1.4%) |
6 (2.7%) |
| 1 Patients were also treated with warfarin
sodium commencing within 24-48 hours of tinzaparin sodium or standard
heparin therapy. |
| 2 All randomized patients who received at
least one dose of active study drug |
| 3 TE = thromboembolic events (DVT and/or
PE) |
| 4 The 95% Confidence Interval (CI) for the
total TE event rate difference (4.0%) was 0.07%, 8.07%. |
Mortality with INNOHEP was 4.6% (10 patients) and with heparin 9.6% (21 patients). The 95%
confidence interval (CI) for the mortality difference was 0.16%, 9.76%.
In a multicenter, open-label, randomized clinical trial INNOHEP was compared to unfractionated
heparin as initial treatment for hospitalized patients with symptomatic PE not requiring thrombolytic
therapy, embolectomy, or vena cava interruption. Patients were excluded if they carried an
unusually high risk for thromboembolic and/or bleeding events or other complications. Of the 608
patients treated, 422 had documented DVT. Prior to determination of study eligibility and
randomization, patients were allowed to receive unfractionated heparin; 78% of the patients
received unfractionated heparin at therapeutic doses for up to 24 hours, and an additional 4%
received heparin at therapeutic doses for greater than 24 hours. After randomization, INNOHEP
was administered SC once daily, 175 IU/kg body weight; heparin as an initial IV bolus (50 IU/kg)
followed by continuous IV infusion with the rate adjusted according to the aPTT (2 to 3 times
control value). For both groups, treatment continued for approximately 8 days. All patients also
Thromboembolic events were infrequent for both treatment groups. No difference was observed
between the two treatment groups for incidence of recurrence of thromboembolic events.
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