AN OVERVIEW ON ASENAPINE MALEATE: PK-PD, PRECLINICAL AND CLINICAL UPDATE

Sanjay Kumar Singh, Ramoji Kosuru, Hitesh Kumar Dewangan and Sanjay Singh*

Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University) Varanasi 221005, India

E-mail: [email protected]

Abstract: Schizophrenia and bipolar disorder are both prevalent types of psychiatric illness in World. The second-
generation antipsychotics have become more viable first-line treatment options. Asenapine is a second-generation (atypical)
antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes. The preclinical and
clinical data suggest that asenapine shown antipsychotic activity with very low extra pyramidal side effect. Asenapine is
available in 5 mg and 10 mg sublingual tablets and administered twice daily with a maximum daily dose allowed up to 20
mg. Patient is advised not eat or drink for 10 minutes after drug administration. The sublingual and oral absolute
bioavailability of Asenapine at 5 mg is 35% and < 2%, respectively. Asenapine is highly bound to plasma protein (95%)
with large volume of distribution (~20-25 l/kg). Higher variability in plasma concentration of asenapine may be observed if
co-administered with CYP1A2 inducers or inhibitor. The other limitations associated with asenapine include non-adherence
patient compliance with dosage form. Apart from these limitations, It may be a suitable treatment option in patients with
increased risk of metabolic disturbances, diabetes or obese. Furthermore, it may, also be a safer alternative in patients with
impaired renal function due to no dose adjustments are required in these individuals (as is the case with risperidone and
paliperidone).

Keywords: Asenapine, Schizophrenia, Bipolar disorder, Second generation antipsychotic.

1. INTRODUCTION have a relapse rate of 40%, while those who discontinue

their treatment have a 1-year relapse rate of 65% and in 2-
Schizophrenia is severe chronic debilitating brain year rate more than 80% [5].
disease affecting approximately 1-2% of the world
population, more affecting the urban population than rural Asenapine (ASN) is claimed to be a novel
population and affecting man and women equally [1]. In psychopharmacologic agent with high affinity and potency
India, the number of patient affected by the schizophrenia is for blocking dopamine, serotonin, -adrenergic and
around 8.3 to 10.7 million. Age of onset is generally histamine receptors, and no appreciable activity at
between 20 year to 35 year and it is characterized by muscarinic cholinergic receptors. The mechanism of action
positive symptoms (e.g., hallucinations, delusions and of asenapine, like other atypical antipsychotics is believed to
thought disorder), negative symptoms (e.g., decits in social be mediated through a combination of antagonist activity at
interaction, emotional expression and motivation) and 5-HT2A and D2 receptors. It is approved for the treatment
cognitive dysfunction (e.g., impairments of attention and of adults with schizophrenia and as an adjunctive therapy
working memory). Schizophrenia has devastating effects on with lithium or valproate for the acute treatment of manic or
several aspects of the patients life. It is among the top ten mixed episodes associated with bipolar I disorder [6].
causes of disability world-wide and reduces the life span of Asenapine has been developed as a structural modification
those afflicted by an average of ten years. Suicide is the of the atypical antidepressant mianserin [7]. It is the first
single greatest cause of premature death among patients antipsychotic drug to be administered through a sublingual
with this disorder. In schizophrenia treatment, patient non- route of administration. It is available in 5 and 10 mg
adherence is a major problem occurred as side effect sublingual tablet dosage form and administered twice daily
associated with drug and long term therapy regimen. More with a maximum daily dose allowed up to 20 mg. Each
than 34% of patient demonstrate adherence problems during tablet can be placed sublingual or buccal as long as it is not
the first 4-6 weeks of treatment and within 2 years its swallowed, should be allowed to dissolve completely, and
reached upto 74% [2-4]. The most common outcomes of the patient should not eat or drink for 10 minutes after drug
non-adherence are usually a remitting course with one or administration [8].
multiple relapses in 50-92% of cases. Patients on medication

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 The objective of this article was to provide a short and sparingly soluble in 0.1 M HCl. It was developed by
overview on asenapine. Here, the pharmacokinetic, Organon laboratories (Org 5222) having CAS registry
pharmacodynamic, preclinical and clinical profiles are number 85650-56-2. The molecular formula of asenapine
presented and discussed. maleate is C17H16CINO.C4H4O4 with a molecular weight
of 401.84 (285.8 as the free base). Asenapine is quite stable
2. PHYSICO-CHEMICAL PROPERTIES in crystalline form, although excessive light can induce
degradation [7]. The pKa of the protonated free base is 8.51.
Asenapine maleate is chemically (3aR*,12bR*)-5-
Log P for neutral species and cationic species is 4.9, 1.4,
Chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz [2,3:6,7]
respectively. The melting point of Asenapine maleate is
oxepino[4,5-c] pyrrole maleate. It is a white to off-white
139.9 C (mp 141-145 C) [9, 10].
non hygroscopic powder which is slightly soluble in water
Table 1: Drug Summary [9].

Chemical Structure
N O
H
H . OH
OH
Cl
O
O
Molecular weight of free base (salt) 285.8 (401.8) g/ moles
Melting point 141-145 C
Solubility (water) Slightly soluble
Solubility (methano, ethanol and Freely soluble
acetone)
Intrinsic dissolution rate in water 123 mg/m2s
pKa of free base 8.51
pKa of maleic acid pK1= 3
pK2=7.52
Log P of free base 6.33
Caco-2 cell permeability 0.9-2.3 x 10

3. PHARMACOKINETICS

3.1 Absorption

Asenapine is absorbed rapidly on oral or gastric mucosa. water and food markedly affect the sublingual and oral
The apparent permeability of asenapine through the Caco-2 bioavailability [12].
cell monolayer was found to be 1x10-5cm/sec. After
sublingual administration; the peak plasma concentration 3.2 Distribution
was obtained within 0.5 to 1.5 hours. The absorption is non
Asenapine is rapidly distributed and has a large volume
linear with dose, increasing the dose two fold (5 to 10 mg
of distribution (~20-- 25 l/kg), indicating extensive extra
twice daily) results in a less than linear (1.7 times) increase
vascular distribution. Asenapine is highly bound (95%) to
in both the extent of exposure and maximum
plasma proteins, including albumin and 1-acid
concentration. The sublingual and oral absolute
glycoprotein. Asenapine and its metabolite N-desmethyl
bioavailability of Asenapine at 5 mg is 35% and < 2%
asenapine are weak substrates of the human P-gp, resulting
respectively [11]. Low oral bioavability was due to high
very less impact on in-vivo disposition of asenapine and N-
hepatogastrointestinal first-pass metabolism. However, the
desmethyl asenapine. The autoradiography of radioactive
oral bioavailability was also low in animals, i.e. between
asenapine revealed that both asenapine and its N-
20-65% in rats and up to 10% in dogs. The presence of

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 desmethyl metabolite penetrate the blood-brain-barrier and pharmacokinetics of asenapine was similar in Caucasian and
accumulate in brain up to 3 h post dosing. Asenapine Japanese subjects [11, 14].
accumulated to a greater extent, with a brain-to-tissue ratio
of 19 at 3 hr post dosing [11, 12]. Article Highlight:
Asenapine is first approved sublingual tablet for
3.3 Metabolism and Excretion treatment of Schizophrenia and Bipolar disorder.
Human sublingual bioavailability is 35% for 5
Direct glucuronidation by UGT1A4 and oxidative mg tablet. However oral bioavailability is < 2%
in human, 20-65% in rats and up to 10% in dogs.
metabolism by cytochrome P450 isoenzymes
Asenapine is active moiety for antipsychotic
(predominantly CYP1A2) are the primary metabolic activity due to its property to cross blood brain
pathways for asenapine. The caution should be taken barriers as compared to metabolite.
when using CYP1A2 inducers (carbamazepine or The caution should be taken when using
rifampin) or CYP1A2 inhibitors (fluvoxamine, CYP1A2 inducers (carbamazepine or rifampin)
ciprofloxacin, ketoconazole). Asenapine is metabolized or CYP1A2 inhibitors.
into two inactive compounds: N-glucuronide-asenapine Due to its well tolerated in nature, no dose
adjustment is required in elderly or renal
and N-desmethyl-asenapine [13]. After administration of
impairment patient.
a single dose of [14C] labeled asenapine, about 90% of the Caution should be taken when using CYP1A2
dose was recovered; approximately 50% was recovered in inducer or CYP1A2 inhibitors with Asenapine.
urine, and 40% recovered in feces. Following an initial
rapid-distribution phase, the mean t was reported to be
24 h. Asenapine is an active moiety, however other 4. PHARMACODYNAMIC
metabolites have negligible effects due to their lower
The precise mechanism of action of asenapine in the
affinity towards dopamininergic and serotonergic
treatment of schizophrenia is not clearly known. Asenapine
receptors [12, 14]).
has similar receptor binding profile of other second-
3.4 Population Pharmacokinetic generation antipsychotic drugs, exhibit potent antagonism at
serotonin, dopamine, noradrenaline and histamine receptors.
In population pharmacokinetic studies, the higher C max Asenapine appears to have relatively higher potency at
and AUC were observed in elderly as compared to adult serotonin receptors than at dopamine receptors. It is
patient might be credited to slow drug clearance. In older hypothesized that the efficacy of asenapine is mediated
population the asenapine Cmax values were 12% higher through a combination of antagonist activity at the
with 5 mg BID and 21% higher with 10 mg BID. AUC dopamine D2 and serotonin 5-HT2A receptors. This unique
(0-12 h) values were 21% higher with 5 mg BID and 30% receptor signature and functional activity of asenapine
higher with 10 mg BID. As per label information, no dose supports its distinct psychopharmacological profile for the
adjustment is required in elderly patient although slow improved treatment of schizophrenia and bipolar mania [15,
drug clearance. The safety and efficacy of asenapine have 16] .
not been established in pediatric population.
Further study of the receptor activity of asenapine suggested
Potential gender differences in asenapine pharmacokinetics that it has an upregulating effect on D1-like receptors, most
have not been studied in a dedicated trial; however in a likely secondary to direct blockade of these receptors. This
population analysis, no significant differences between men finding is important because some evidence suggests that
and women on asenapine pharmacokinetics were observed. the upregulation of D1and D2 receptors is associated with a
Although in a population pharmacokinetic analysis a 14% decreased likelihood of producing extrapyramidal symptom
decrease in clearance was observed in Black subjects (EPS)related adverse events. This finding is different from
compared with subjects from other ethnic origins, the those of other antipsychotics, such as fluphenazine,
magnitude of this effect is small in relation to the overall olanzapine, and risperidone, which do not significantly
variability in pharmacokinetics observed for asenapine. The cause a variation in D1-receptor levels [17, 18].
product label concludes that no effect of race on asenapine
concentrations was observed. In a dedicated study, the

112
5. SAFETY AND TOLERABILITY monitors, which further supports the antipsychotic activity
of this novel agent [24].
The majority of efficacy studies indicate that asenapine is
generally well tolerated. The most common adverse effects Apomorphine-induced disruption of prepulse inhibition of
that associated with asenapine are somnolence, dizziness, the startle reflex (PPI):
weight gain and extrapyramidal symptoms (EPS) dose
relationship. Rates of EPS with asenapine treatment Administration of asenapine (0.1-- 1.0 mg/kg), significantly
reported lower than with haloperidol and lower or and dose-dependently increased startle response in
equivalent to risperidone [19]. The lesser affinity for D2 apomorphine-pretreated compared to vehicle-pretreated rats.
receptors offers a benefit by decreasing the risk of EPS and The potency of asenapine in reversing apomorphine-induced
hyper prolactinemia as seen with potent drugs such as disruption of PPI was higher than that of olanzapine and
haloperidol. Whereas, the risk of EPS was higher in risperidone, which probably reflects its higher affinity for
asenapine compared with olanzapine, with a 35.4% D2 receptors [24, 25].
increased incidence with asenapine versus 19% with
Catalepsy:
olanzapine [20]. Although there is a risk of weight gain with
asenapine but it is lesser than that associated with This animal test predicts the ability of a drug to induce EPS,
olanzapine. This has been attributed to the lower binding and in particular Parkinsonism. In this test, animals are
affinity of asenapine for the histamine receptor (H1) as placed on an inclined grid and the amount of time the
compared to olanzapine and quetiapine which have strong animal remains immobile after drug or vehicle treatment is
H1 binding affinity and thereby carry a greater risk of calculated. Lower doses of asenapine (0.1 and 0.2 mg/kg)
weight gain. Elevated fasting glucose and cholesterol did not induce cataleptic behaviors. A higher dose of
elevation may occur in some patients as with other atypical asenapine (0.5 mg/kg), which is 2.5 times the effective
antipsychotics [13]. It may induce orthostatic hypotension antipsychotic dose of asenapine in CAR, produced catalepsy
and syncope because of its 1-adrenergic antagonist 60-120 min after administration. These findings suggest that
activity, though these adverse events were limited in both asenapine exhibits a fairly benign EPS profile, but it may
schizophrenia (0.2%) and bipolar mania (0.3%) patients induce EPS in patients at doses higher than optimal
[21]. therapeutic doses [23, 26].

6. PRECLINICAL EFFICACY Chronic mild stress (CMS):

Asenapine were assessed in different animal model to Repeated treatment with asenapine reversed the CMS
evaluate antipsychotic activity for Schizophrenia and induced reduction in sucrose consumption in a dose-
Bipolar disorder [22]. dependent manner. This reversal was similar to that
observed after treatment with the standard antidepressant
Conditioned avoidance response (CAR):
imipramine. The mechanism behind asenapines potential
Asenapine (0.05, 0.1, and 0.2 mg/kg) was active in this antidepressant activity is remains unclear. However, recent
model as it showed dose-dependent suppression of CAR, evidence suggesting that serotonin 5-HT2C and 5-HT7
with the highest doses producing profound and sustained receptors play a role in mediating the actions of
suppression of CAR for 90 min after administration. The antidepressant drugs, and the high affinity and selectivity of
median effective dose (ED50) for 80% CAR suppression asenapine for both receptor subtypes, suggests that these
was 0.12 mg/kg, which supports asenapines ability to block novel targets may mediate, at least in part, the
D2 receptors [23]. antidepressant actions of asenapine [27, 28] .

Amphetamine-induced locomotor activity: 7. CLINICAL EFFICACY IN SCHIZOPHRENIA AND

BIPOLAR DISORDER
Administration of asenapine (0.1-- 1.0 mg/kg) prior to the
injection of amphetamine (1.0 mg/kg) dose-dependently Asenapine may be useful alternative treatment option in the
blocked D2 receptors and reversed amphetamine-induced management of schizophrenia and bipolar I disorder. It has
locomotor activity in adult rats when assessed in activity shown efficacy in the treatment of schizophrenia and mixed
or manic episodes associated with bipolar I disorder in

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short- and long-term trials. Asenapine appears to be well dosing for most other antipsychotic. The twice-daily dosing
tolerated. It has a low propensity for causing antimuscarinic requirement confers its own disadvantage independent of
adverse effects because of its lack of appreciable binding to the sublingual administration, as increases in dosing
muscarinic receptors. Its atypical pharmacological profile frequencies seem to have a significant negative effect on
(high 5HT2A:D2 affinity ratio) also suggests a low risk of schizophrenia patients adherence to antipsychotic
EPS-related adverse effects. Asenapine effects on prolactin medication regimens. Apart from above issues, Asenapine
and metabolic parameters are modest and it has a more sublingual tablets are a new option for the treatment of acute
favourable weight gain profile than olanzapine. It may episodes of schizophrenia and for the treatment of acute
therefore be a suitable treatment option in patients who are manic or mixed episodes of bipolar I disorder.
at increased risk of metabolic disturbances or diabetes or
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