Transcript Serum levels of aripiprazole and dehydroaripiprazole, clinical

Serum levels of aripiprazole and
dehydroaripiprazole, clinical
response and side effects
Linas Martinaitis
Erasmus =)
Abstract (1)
• Aripiprazole, a novel antipsychotic drug, is metabolized by
CYP3A4 and CYP2D6 forming mainly its active metabolite
dehydroaripiprazole.
• In this study, aripiprazole and dehydroaripiprazole serum levels of
psychiatric patients were measured and related to dose,
comedication, and clinical effects including therapeutic and side
effects.
• Patients were treated with mean doses of 20 +/- 8 mg/day of
aripiprazole (median 15 mg, range 7.5-60 mg).
• Serum levels correlated significantly with the dose (r = 0.419; P
< 0.01), with a mean value of aripiprazole of 214 +/- 140 ng/ml.
• Mean concentrations of the active metabolite
dehydroaripiprazole amounted to 40% of the parent compound.
• Comedication with CYP3A4 and CYP2D6 inducers or inhibitors
changed serum levels up to 51%.
Abstract (2)
• Improvement was best in patients with a serum level
between 150 and 300 ng/ml.
• No or only mild side effects were detected in patients,
with aripiprazole plasma concentrations between 110 and
249 ng/ml.
• A total of 32% of the patients who received no other
antipsychotic drug besides aripiprazole reported side
effects; tension being the most frequent one.
• Since serum levels of aripiprazole and
dehydroaripiprazole were highly variable between
individuals, and distinct ranges were associated with
good therapeutic response and minimal side effects, it
seems likely that therapeutic drug monitoring can be
helpful to improve the antipsychotic drug therapy.
Introduction
• Aripiprazole is a novel antipsychotic drug with an improved
pharmacological profile for the treatment of acute and chronic
schizophrenia. In contrast with other antipsychotic agents,
aripiprazole acts as a partial agonist at D2 receptors, a partial
agonist at 5-HT1A and an antagonist at 5-HT2A receptors.
• Dopamine-serotonine system stabilizer which is active against
positive and negative symptoms of schizophrenia with low risk of
side effects.
• Aripiprazole is metabolized in liver by the cytochrome P450
isoenzymes (CYP) 3A4 and 2D6 with an elimination half-life 5080 h.
• The major metabolite, dehydroaripiprazole, is an active
compound with a similar pharmacodynamic profile. T1/2 = 94 h.
• Due to extensive metabolism and interindividual variability in
expression of CYP enzymes, blood levels are expected to vary in
population.
• => Therapeutic drug monitoring (TDM)
Materials and methods
• Patients: 283 pts; 164 diagnosed with a schizophrenic
disorder; 75 of them on monotherapy.
Other patients suffered from schizoaffective disorder,
affective disorder, and borderline personality disorder.
M/F: 109/55. Mean age 33,8 years (19-66).
• Severity of illness and patient outcome were assessed on
the day of blood withdrawal according to the Clinical Global
Impressions scale (CGI). Mean initial CGI was 6,0.
• Determination of drug serum levels: blood samples were
collected early in the morning before the first daily dose, at
least 12 h after last drug intake to obtain trough
concentrations. Analyses were performed with HPLC.
Levels were measured under steady state conditions at the
earliest 2 weeks after start of aripiprazole therapy.
Results: PK
• Significant serum level to do dose correlations for aripiprazole
(r=0,419; P<0,01), dehydroaripiprazole (r=0,355; P<0,01) and
their total sum (r=0,482; P<0,01).
• The mean concentration to dose (C/D) ratio was 11,4±7,3
ng/ml/mg for aripiprazole [A] and 4,0±4,0 ng/ml/mg for
dehydroaripiprazole [dA] in patients who received no additional
drugs that are inhibitors or inducers of CYPs.
• +metoprolol [inhibitor of CYP2D6]
=> ↑ 40% A and ↑ 56% dA serum C/D.
• +fluvoxamine [inh. CYP1A2, 2C9, 2C19, 3A4]
=> ↑ 51% A and ↑ 120% dA.
• +fluoxetine [inh. CYP2C9, 2C19, 2D6, 3A4] => slightly ↑ A.
• +paroxetine [inh. CYP2D6] => similar to control.
• +carbamazepine [inducer of CYP1A2, 2C9, 2C19, 3A4]
=> ↓ 64% A, but the effects did not reach significance.
Results: PD (1)
• Pharmacodynamic analyses were restricted to 164 schizophrenic
patients.
• Doses of 15 and 30 mg/d. were given most frequently, and
application rates ranged from 7,5 to 60 mg/d.
• Mean aripiprazole serum level was 214 +/- 140 ng/ml,
dehydroaripiprazole – 78 +/- 59 ng/ml.
• Of the patients receiving aripiprazole as antipsychotic
monotherapy (n=74), 60% were rated as very much or much
improved.
• Defining these patients as responders to A, their 25th and 75th
percentile serum levels ranged 124 to 286 ng/ml of A. This
indicated that 150-300 ng/ml could be a target range for the drug.
• In patients receiving 150-300 ng/ml of A the response rate was
68%. <150 ng/ml - 57%; >300 ng/ml - 50%.
• Regarding concentrations of dehydroaripiprazole or the total
amount of parent substance plus metabolite, optimal blood levels
could not be deduced.
Results: PD (2)
• For 32% of the 74 patients under antipsychotic
monotherapy, side effects were reported:
― Tension 8%
― Sedation 7%
― Extrapyramidal 7%
― Gastrointestinal 3%
― Cardiovascular 3%
― Skin irritation 1%
― Urogenital 1%
― Blurred vision 1%
• No or mild side effects could be detected in patients with
aripiprazole serum level between 110 and 249 ng/ml (25th to
75th percentile), with a mean value of 194 +/- 125 ng/ml.
• Serum levels of patients, who suffered from moderate to
severe side effects, ranged between 210 and 335 ng/ml for
aripiprazole with a mean value of 296 +/- 151 ng/ml.
Discussion (1)
• C/D correlation significant, nevertheless the spread was
wide. Why?
— Intrinsic factors: genetic polymorphisms of CYPs, age, morbidity.
— Extrinsic factors: smoking, food constituents.
• Moderate interaction potential of A and dA with CYP2D6 &
3A4 inhibitors and inducers. However, only effects of
metoprolol were significant: ↑ up to 51% of A and ↑ up to
120 % of dA.
• Taking into account supportive results of other studies, daily
dose of A should be reduced to a half when taken with
strong CYP2D6 & 3A4 inhibitors (metoprolol, itraconazole,
quinidine).
• Due to the high inter-individual variability of serum
concentrations it is preferable to control blood in patients
comedicated with CYP2D6 or 3A4 instead of blind dose
adaptation.
Discussion (2)
• Improvement in CGI score was 2,2.
• Other studies: 3,2; 2,17; 3,5. => long-term
• Our patients were more severely ill: 6,0 compared to 4,3
and 4,8.
• Optimal serum concentrations: 150-300 ng/ml => 68%
responders with at least much improvement according to
CGI.
• With inclusion of serum levels of dA or the sum the
concentration-response relationships were less clear.
Therefore and because of the high variability between
patients in the metabolite to parent drug ratio, determination
of only A serum levels seems to be sufficient for treatment
optimization by TDM.
Discussion (3)
• Aripiprazole was well tolerated in our patients with
an overall side effect rate of 32%.
• Frequency of EPS was as low as in other studies –
7%, which is comparable to placebo.
• Data obtained from this investigation may be used
for orientation to confirm or revise the reported
plasma concentrations considered to be optimal for
treatment.
• It seemed unlikely that consideration of dA is
necessary for treatment optimization, but it can
probably be helpful for evaluation of the CYP2D6 &
3A4 phenotype.
Thank you!!