Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
It has been proposed that the neuropharmacological profile of sertindole, as an antipsychotic drug, is derived from its selective inhibitory effect on mesolimbic dopaminergic neurons and is due to balanced inhibitory effects on central dopamine D 2 and serotonin 5HT 2 receptors as well as on α 1 -adrenergic receptors.

In animal pharmacology studies, sertindole inhibited spontaneously active dopamine neurons in the mesolimbic ventral tegmental area (VTA) with a selectivity ratio of more than 100 compared to dopamine neurons in substantia nigra pars compacta (SNC). Inhibition of SNC activity is thought to be involved in movement side effects (EPS) associated with many antipsychotic drugs.

Antipsychotic drugs are known to increase serum prolactin levels through dopamine blockade. The prolactin levels in patients receiving sertindole remained within normal limits, both in short-term studies and during long-term treatment (one year).
However hyperprolactinaemia and prolactin related events have occasionally been reported with post-marketing sertindole use.

Sertindole has no effect on muscarinic and histaminic H 1 receptors. This is confirmed by the absence of anticholinergic and sedative effects related to those receptors.

Further information on clinical trials
The Sertindole Cohort Prospective Study (SCoP) was a multi national study conducted as a large simple trial under normal conditions of use, comparing all-cause mortality, the cardiac safety and suicidality of sertindole to that of risperidone. The study was designed as a prospective, randomised, 

partially blinded study with two parallel groups; sertindole (n=4930) and risperidone (n=4928) with treatment periods up to 4 years.

The all-cause mortality (the first primary endpoint) was similar for both sertindole and risperidone.
The causes of death differed between the two treatment groups. The leading cause of death in patients treated with sertindole was cardiac, with a significantly higher risk of cardiac mortality than in the risperidone group. A lower risk of suicide attempts was seen in patients treated with sertindole, although the risk of completed suicide was not significantly different between the two groups.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties
Elimination of sertindole occurs via hepatic metabolism, with a mean terminal half-life of approximately 3 days. The clearance of sertindole decreases with multiple dosing to a mean around 14 l/h (females have approximately 20% lower apparent clearance than males, although lean-mass corrected clearances are comparable). Therefore, upon multiple dosing, accumulation is greater than predicted from a single dose, due to an increase in the systemic bioavailability. However, at steady state, clearance is dose independent and plasma concentrations are proportional to dose. There is moderate inter-subject variability in sertindole pharmacokinetics, due to the polymorphism in the cytochrome P450 2D6 (CYP2D6). Patients who are deficient in this hepatic enzyme have sertindole clearances that are ½ to ⅓of those who are CYP2D6 extensive metabolisers. These poor metabolisers (up to 10% of the population) will therefore have plasma levels 2 - 3 times the normal. Sertindole concentration is not predictive of therapeutic effect for an individual patient; thus, dosing individualisation is best achieved by assessment of therapeutic effect and tolerability.

Absorption
Sertindole is well absorbed with a t max of sertindole after oral administration of approximately 10 hours. Different dose strengths are bioequivalent. Food and aluminium-magnesium antacids have no clinically significant effect on the rate or the extent of sertindole absorption.

Distribution
The apparent volume of distribution (V β /F) of sertindole after multiple dosing is approximately 20 l/kg. Sertindole is about 99.5% bound to plasma proteins, primarily to albumin and α 1 -acid glycoprotein. In patients treated with recommended doses, 90% of the measured concentrations are below 140 ng/ml (∼320 nmol/l). Sertindole penetrates into red blood cells with a 1.0 blood/plasma ratio. Sertindole readily penetrates the blood-brain and placental barriers.

Metabolism
Two metabolites have been identified in human plasma: dehydrosertindole (oxidation of the imidazolidinone ring) and norsertindole (N-dealkylation). Concentrations of dehydrosertindole and norsertindole are approximately 80% and 40%, respectively, of the parent compound at steady state.
Sertindole activity is primarily due to the parent drug and the metabolites do not appear to have significant pharmacological effects in humans.

Excretion
Sertindole and its metabolites are eliminated very slowly, with a total recovery of 50-60% of a radiolabelled oral dose 14 days after administration. Approximately 4% of the dose is excreted into the urine as parent drug plus metabolites of which less than 1% is present as parent drug. Faecal excretion is the major route of excretion and accounts for the rest of the parent drug and metabolites.