Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Combination of platelet aggregation inhibitors
ATC codes:
1. B01AC07
2. B01AC06

Dipyridamole
Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo. This inhibition, which is dose-dependent at therapeutic concentrations (0.5 - 2 µg/ml) and which reaches a maximum of about 80%, leads to increased local extracellular concentrations of ade- nosine acting on the platelet A2 receptor. The adenosine stimulates platelet adenylate cyclase and in- creases platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels, thereby inhibiting platelet agg- regation induced by various stimuli such as platelet-activating factor (PAF), collagen and adenosine diphosphate (ADP). The decreased platelet aggregation reduces platelet consumption to normal lev- els. Adenosine also has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation.

In stroke patients, dipyridamole has also been shown to decrease the density of prothrombotic surface proteins (PAR-1 thrombin receptor) on platelets and reduce blood levels of C-reactive protein (CRP) and von Willebrand factor (vWF). In-vitro studies have shown that dipyridamole selectively inhibits gene expression of the inflammatory cytokine MCP-1 (monocyte chemoattractant protein-1) and rel- ease of the plaque-destabilising enzyme MMP-9 (matrix metalloproteinase-9), both of which factors arise from platelet-monocyte interaction.
Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. cAMP-PDE is only weakly inhi- bited but, at therapeutic concentrations of dipyridamole, cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE) is inhibited to a marked degree. The reduced breakdown of cGMP that this entails leads to an increase in platelet cGMP via the enhanced stimulatory action of endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide.

Dipyridamole increases the release of tissue plasminogen activator (t-PA) from microvascular endoth- elial cells and dose-dependently enhances the antithrombotic properties of endothelial cells on throm- bus formation on adjacent subendothelial matrix. Dipyridamole is a potent radical scavenger for oxy and peroxy radicals.

Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium.

Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the concentrat- ion of the protective mediator 13-HODE (13-hydroxyoctadecadienoic acid).

ASA
ASA inhibits collagen-induced platelet aggregation by the irreversible acetylation of the enzyme com- plex cyclooxygenase (COX). This enzyme is also found in platelets and endothelial cells and produ- ces the precursors (endoperoxides) for prostaglandin and thromboxane biosynthesis. In endothelial cells, the main product of the endoperoxides is prostacyclin, a powerful vasodilator and inhibitor of platelet aggregation. Platelets, on the other hand, form large quantities of thromboxane A2, which in- duces aggregation and has a vasoconstrictor effect. The (indirect) inhibition of thromboxane formati- on by ASA is therefore the cause of the inhibition of collagen-induced platelet aggregation which has been detected in vitro and ex vivo. The inhibition of cyclooxygenase in endothelial cells is not perma- nent, unlike in platelets, since new enzyme is formed as a result of protein biosynthesis. However, in the anuclear platelets, which have a survival time of 8 - 10 days, virtually no protein synthesis takes place and the enzyme remains inhibited for the whole of the platelet's life. This is the reason for the cumulative inhibitory effect on platelet aggregation achieved by repeated doses of ASA 
Combination of dipyridamole and ASA
The in-vitro and ex-vivo biochemical and pharmacological studies described confirm that dipyridamole has antithrombotic effects which are independent of the inhibition of thromboxane formation by ASA.
Since the formation of a thrombus involves the close interaction of a number of different prothrombo- tic stimuli, it is rational to combine two molecules with different antithrombotic mechanisms of action (which dipyridamole and ASA have been shown to have) in order to achieve greater antithrombotic ef- ficacy.

Clinical efficacy

Aggrenox was studied in a double-blind, placebo-controlled, 24-month trial (European Stroke Preven- tion Study 2; ESPS-2) carried out in 6602 patients who had had an ischaemic stroke or transient isch- aemic attack within three months prior to entry. Patients were randomised to one of four treatment gr- oups: Aggrenox (ASA 25 mg and prolonged-release dipyridamole 200 mg), prolonged-release dipyrid- amole 200 mg alone, ASA 25 mg alone or placebo. Patients received one capsule twice daily, morn- ing and evening. Efficacy assessments included analyses of stroke (fatal or non-fatal) and death (fr- om all causes) as confirmed by a blinded morbidity and mortality assessment group. In ESPS-2, Ag- grenox reduced the risk of stroke by 23.1% compared to ASA 50 mg/day (p = 0.006), by 24.7% com- pared to prolonged-release dipyridamole 400 mg/day (p = 0.002) and by 37.0% compared to placebo (p < 0.001).

The results of the ESPS-2 trial are supported by the European/Australasian Stroke Prevention in Re- versible Ischaemia Trial (ESPRIT), which studied a combination of dipyridamole 400 mg/day (with 83% of patients receiving the prolonged-release form of dipyridamole and 8% receiving Aggrenox) and ASA 30 - 325 mg/day. A total of 2739 patients who had had an ischaemic stroke of arterial orig- in were treated, with 1376 allocated to ASA alone and 1362 to ASA plus dipyridamole. The primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myo- 

cardial infarction or major bleeding complications. Patients in the ASA plus dipyridamole group sh- owed a 20% risk reduction (p < 0.05) for the primary composite endpoint compared to those in the ASA group (13% vs. 16%; hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.66 - 0.98).

The PRoFESS (PRevention Regimen For Effectively avoiding Second Strokes) trial was an internat- ional randomised, parallel-group, double-blind, double-dummy, 2x2 factorial trial comparing Aggre- nox with clopidogrel, and telmisartan with matching placebo, in the prevention of stroke in patients who had previously experienced an ischaemic stroke of non-cardioembolic origin. A total of 20,332 patients were randomised to Aggrenox (n = 10,181) or clopidogrel (n = 10,151), which were both gi- ven on a background of standard treatment. The primary endpoint was the time to first recurrence of stroke of any type.

The incidence of the primary endpoint was similar in the two treatment groups (9.0% for Aggrenox vs.
8.8% for clopidogrel; HR 1.01, 95% CI 0.92 - 1.11). No significant differences between the Aggrenox and clopidogrel groups were detected for several other important pre-specified endpoints, including the composite of recurrent stroke, myocardial infarction or death due to vascular causes (13.1% in both treatment groups; HR 0.99, 95% CI 0.92 - 1.07) and the composite of recurrent stroke or major haem- orrhagic event (11.7% for Aggrenox vs. 11.4% for clopidogrel; HR 1.03, 95% CI 0.95 - 1.11). The fu- nctional neurological outcome three months post-recurrent stroke was assessed by the modified Rank- in Scale (mRS); no significant difference in the distribution of the mRS score between Aggrenox and clopidogrel was observed (p = 0.3073 by Cochran-Armitage test for linear trend).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
There is no relevant pharmacokinetic interaction between the dipyridamole in the prolonged-release pellets and the ASA. The pharmacokinetics of Aggrenox can therefore be described in terms of the pharmacokinetics of the individual components.

Dipyridamole
Most of the pharmacokinetic data refer to healthy volunteers.

The pharmacokinetics of dipyridamole have been shown to be dose-linear for all doses used therapeu- tically.

For long-term treatment, capsules containing prolonged-release dipyridamole pellets were developed.
The solubility of dipyridamole shows a pH dependence which prevents the drug from dissolving in the lower gastrointestinal tract. As prolonged-release preparations depend on continued drug absorption in the higher pH environment of the lower gastrointestinal tract, the dipyridamole was combined with tartaric acid. Prolonged release of the dipyridamole is achieved with the aid of a diffusion membrane which is sprayed onto the pellets.

Various pharmacokinetic studies at steady state showed that all parameters which are suitable for char- acterising the pharmacokinetic properties of prolonged-release preparations are equivalent or somewh- at improved following prolonged-release dipyridamole twice daily compared to immediate-release di- pyridamole tablets three or four times daily; bioavailability is slightly higher, peak plasma levels are similar, trough plasma levels are considerably higher and the peak-trough difference is smaller.

Absorption
Absolute bioavailability is about 70%. As about a third of the dose is removed by first-pass metabol- ism, it can be assumed that dipyridamole is almost completely absorbed following administration of Aggrenox.

After a daily dose of 400 mg dipyridamole in the form of Aggrenox (200 mg twice daily), peak plasma levels are reached about 2 - 3 hours following administration. The mean peak plasma level at steady state is 1.98 µg/ml (1.01 - 3.99 µg/ml) and the mean trough level at steady state is 0.53 µg/ml (0.18 - 1.01 µg/ml). Food intake has no relevant effect on the pharmacokinetics of the prolonged-release di- pyridamole in Aggrenox.


Distribution
Dipyridamole is highly lipophilic (log P = 3.92 (n-octanol/0.1N NaOH)) and is therefore distributed to many organs.
In animals, dipyridamole is distributed preferentially to the liver, then to the lungs, kidneys, spleen and heart. The rapid distribution phase observed following intravenous administration is not seen follow- ing oral administration.
The apparent volume of distribution of the central compartment (Vc) is about 5 litres (similar to plas- ma volume). The apparent volume of distribution at steady state (Vss), reflecting distribution to vari- ous compartments, is about 100 litres.

Dipyridamole does not cross the blood-brain barrier to any appreciable extent.

Dipyridamole crosses the placenta only in very small quantities. In one woman studied, the concentr- ation of dipyridamole in breast milk was found to be 1/17th of the plasma concentration.

Binding of dipyridamole to proteins is about 97 - 99%. The substance is primarily bound to 1-acid glycoprotein and albumin.

Metabolism
Dipyridamole is metabolised in the liver. Metabolism occurs by conjugation with glucuronic acid, pri- marily to monoglucuronide and, to a small extent, to diglucuronide. In plasma, about 80% of the total amount is present as the parent compound and 20% as monoglucuronide. The pharmacodynamic acti- vity of dipyridamole glucuronides is considerably weaker than that of dipyridamole.

Elimination
The dominant half-life following oral administration, as with intravenous administration, is about 40 min.
Renal excretion of parent compound is negligible (< 0.5%) and urinary excretion of the glucuronide metabolite is low (5%). The metabolites are mostly (about 95%) excreted via bile into the faeces, with some evidence of enterohepatic recirculation.
Total clearance is approximately 250 ml/min and mean residence time (MRT) is about 11 h, resulting from an intrinsic MRT of 6.4 h and a mean absorption time of 4.6 h. A prolonged terminal half-life of about 13 h is observed after both intravenous and oral administration. This terminal half-life represe- nts only a small proportion of the total area under the plasma concentration-time curve (AUC) and is thus of relatively minor importance, as emphasised by the fact that steady state is achieved in two days at a dosage of two prolonged-release capsules daily. Repeated administration of Aggrenox does not lead to any significant accumulation.

Kinetics in the elderly
Plasma dipyridamole concentrations, determined as AUC, in elderly patients (> 65 years) were about 50% higher following administration of tablets and about 30% higher following administration of Ag- grenox than in young patients (< 55 years). The difference is caused mainly by lower clearance; abs- orption appears to be comparable. In elderly patients in the ESPS-2 trial, similar increases in plasma concentrations were observed for Aggrenox and dipyridamole tablets 200 mg.

Kinetics in patients with renal impairment
Since renal excretion of dipyridamole is very low (5%), no change in pharmacokinetics is anticipated in patients with renal failure. In ESPS-2 patients, with creatinine clearances ranging from 15 ml/min to > 100 ml/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuron- ide metabolites when data were corrected for differences in age.

Kinetics in patients with hepatic impairment
In patients with liver failure, there is no change in the plasma levels of dipyridamole although levels of the glucuronides, which have weak pharmacodynamic activity, are increased. It is therefore recomm- ended that dipyridamole be given at its normal dosage unless there is clinical evidence of liver failure.

ASA


Absorption
Following oral administration, ASA is rapidly and completely absorbed in the stomach and intestine.
Approximately 30% of the dose is presystemically hydrolysed to salicylic acid. After a daily dose of 50 mg ASA in the form of Aggrenox (25 mg twice daily), peak plasma levels are reached 30 min after administration. Steady-state peak plasma levels of ASA after two 25-mg doses daily were 360 ng/ml.
Peak plasma levels of salicylic acid (about 1100 ng/ml) are attained within 60 - 90 min. Food intake has no relevant effect on the pharmacodynamic activity of the ASA component of Aggrenox.

Distribution
ASA is rapidly converted to salicylate but remains the predominant form of the substance in plasma in the first 20 min after oral administration. Plasma levels of ASA decline rapidly with a half-life of ab- out 15 min. The major metabolite of ASA, salicylic acid, is highly bound to plasma proteins; its bind- ing is concentration-dependent (non-linear). At low concentrations (< 100 µg/ml), approximately 90% of salicylic acid is bound to albumin. Salicylates are widely distributed to all tissues and body fluids, including the central nervous system, breast milk and foetal tissues.

Metabolism
ASA is rapidly metabolised by non-specific esterases to salicylic acid. Salicylic acid is metabolised to salicyluric acid, salicyl phenolic glucuronide, salicyl acyl glucuronide and, to a minor extent, gentisic and gentisuric acids. The formation of the major metabolites salicyluric acid and salicyl phenolic glu- curonide is readily saturable and follows Michaelis-Menten kinetics; the other metabolic routes are fir- st-order processes.

Elimination
ASA has an elimination half-life from plasma of 15 - 20 min. At low doses (e.g. 325 mg), the major metabolite salicylic acid has an elimination half-life of 2 - 3 h; at high doses, this may rise to 30 h be- cause of non-linearity in metabolism and plasma protein binding.
More than 90% of ASA is excreted as metabolites via the kidneys. The fraction of salicylic acid exc- reted unchanged in the urine increases with increasing dose. The renal clearance of salicylate also in- creases with increasing urinary pH.

Kinetics in patients with renal impairment
ASA is contraindicated in patients with severe renal failure (glomerular filtration rate < 10 ml/ min).
An increase in total plasma levels and in the unbound fraction of salicylic acid has been reported.

Kinetics in patients with hepatic impairment
ASA is contraindicated in patients with severe liver failure. An increase in the unbound fraction of sa- licylic acid has been reported.