Sertindole - Antipsychotic Agent- Investigational Drugs
Drug Name:Sertindole - Antipsychotic Agent- Investigational Drugs
List Of Brands:
Indication Type Description:
Indication
Adverse Reaction
Pharmacology/ Pharmacokinetics
Indication:
Psychotic disorders
Summary-
Sertindole should provide an effective and safe alternative treatment when therapy with
traditional antipsychotics have failed due to lack of efficacy or intolerable effects.
Additional trials are necessary to establish the long term safety, especially the
incidence of tardive dyskensia, and efficacy of seritindole.
The drug which is available from Abbott may be -approvable- in 1997
Adverse Reaction:
Side effects-
Adverse effects observed during phase I trials include-
lethargy, drowsiness, nasal congestion, sexual dysfunction, GI complaints, dizziness,
lightheadeness, mild tremor, othostatic hypotension, syncope, dystonia,
postural hypotension and cogwheel rigidity. No patient experienced EPS.
The most common adverse effects experienced during phase II trials that occurred more often with sertindole 20mg/day than placibo included -
Headache 26%, nasal congestion 26%, dry ejaculation 17%, constipation , dizziness,
somnolence 11%. Dry ejaculation was the only side effects that was found to be
significantly greater than placebo (p < 0.05)
Adverse effects experienced during long term study were similar , but incidence
rates were higher.
Pharmacology/ Pharmacokinetics:
Pharmacology-
Sertindole is a new -atypical- antipsychotic agent with unique pharmacologic properties
compared to traditional agents. The mechanism of action of sertindole is via its strong
antagonism of dopamine D2, serotinin 5-HT2, and norepinephrine alpha, receptors.
Sertindole appears to have a low extrapyrimidal symptoms EPS potential, does not
cause anticholinergic effects,, does not inhibit cognitive functioning and has potential
anxiolytic activity.
Pharmacokinetics-
Immunocompromised patients- Sertinadole is slowly absorbed from the GI tract with
a peak plasma concentration acheived after 8 to 12 hours. Following a single dose,
the eliminaton half life is approximately 60 hours, but there is a great patient variability
with 10% of the subjects demonstrating half lives > 100 hours after administration of
a single dose.
Due to sertindoles long half life steady state concentrations are not reached until
after 3 to 4 weeks. The long half life of sertindole should allow for once daily dosing.
Sertindole is characterised by non-linear kinetics. Increasing the dose by 20% can
increase plasma levels by 40%. Sertindole is significantly bound to plasma proteins
(> 90%) with only a small amount of the drug being renally excreted. Therefore, seritindole
will not presumably eliminated by dialysis.
In vitro studies have shown that sertindole is predominently metabolised by the hepatic
cytochrome P450 3A4 isoform system and eliminated by the GI tract. Sertindole has two
metabolites , norsertindole and Lu 28-092, but the activity of these metabolites have not
been established
Clinical trials-
In seven phase I trials over 100 healthy patients received sertindole 0.5 to 32 mg in a single
dose or in escalating dose upto 14 days. These studies demonstrated that overall
seritindole was safe and well tolerated
Three phase II studies examined the efficacy of sertindole in doses upto 4 to 24mg/day.
The first was a pilot , double blind, randomized, placebo controlled , multi-center
study designed to compare the efficacy of sertindole (n=27) and placebo (n=11) in
patients diagnosed with schizophrenia or schizoaffective disorder.
The study concluded that sertindole was effective in most patients at a dose of 16
or 20mg/day and this therapy was associated with minimal adverse effects.
The second and third phase II studies were randomized, double-blind, multi-centered
and placebo controlled with identical study design except that each study had four
different groups, 8, 12 or 20mg/day of sertindole or placebo in the second tial, and
the third study had 4 to 12mg/day sertindole, placbo or haloperidol (eg Hadol)
8mg twice daily.
All patients taking sertindole were titrated upwards starting with 4mg/day and increasing
by 4mg/day every third day until the desired dose was reached. The titration dose lasted
12 days and the maintenance phase period was 28 days. Patients enrolled in both studies
had to have a previous response to antipsychotic drugs
There were 205 patients enrolled in the second trial and 109 in the third, 153 patients
completed at least 13 of the total 40 days of the second trial and were included in the
final analysis( 107 completed the entire study). Only the 20mg sertindole group
significantly improved in all efficacy parameters compared to placebo.
Sertindole 20mg was equally efficacious to haloperidol but caused fewer side effects.
In a long term , open label study, sertindole 4 to 24mg/day was administered to 170
patients for upto 2 years to determine its safety and efficacy. The mean exposure
to sertindole was 121 days ( range 2 to 532 days) and the most common dose
administered was 20mg/day (33%)
