Asenapine - How It Works
Clinical pharmacology details from the US FDA-approved label: how Asenapine works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action The mechanism of action of asenapine in bipolar I disorder is unknown.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of asenapine in bipolar I disorder is unknown.
12.2 Pharmacodynamics Asenapine exhibits high affinity for serotonin 5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-HT 6 , and 5-HT 7 receptors (Ki values of 2.5, 2.7, 0.07, 0.18, 0.03, 1.6, 0.25, and 0.11 nM, respectively), dopamine D 2A , D 2B , D 3 , D 4 , and D 1 receptors (Ki values of 1.3, 1.4, 0.42, 1.1, and 1.4 nM, respectively), α 1A , α 2A , α 2B , and α 2C -adrenergic receptors (Ki values of 1.2, 1.2, 0.33 and 1.2 nM, respectively), and histamine H 1 receptors (Ki value 1 nM), and moderate affinity for H 2 receptors (Ki value of 6.2 nM).
In in vitro assays asenapine acts as an antagonist at these receptors.
Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M 1 ).
12.3 Pharmacokinetics Following a single 5 mg dose of asenapine, the mean C max was approximately 4 ng/mL and was observed at a mean t max of 1 hour.
Elimination of asenapine is primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2).
Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs.
With multiple-dose twice-daily dosing, steady-state is attained within 3 days.
Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.
Absorption: Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours.
The absolute bioavailability of sublingual asenapine at 5 mg is 35%.
Increasing the dose from 5 mg to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration.
The absolute bioavailability of asenapine when swallowed is low (<2% with an oral tablet formulation).
The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased asenapine exposure.
Therefore, eating and drinking should be avoided for 10 minutes after administration [see Dosage and Administration ] .
Distribution: Asenapine is rapidly distributed and has a large volume of distribution (approximately 20 to 25 L/kg), indicating extensive extravascular distribution.
Asenapine is highly bound (95%) to plasma proteins, including albumin and α 1 -acid glycoprotein.
Metabolism and Elimination: Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine.
Asenapine is a high clearance drug with a clearance after intravenous administration of 52 L/h.
In this circumstance, hepatic clearance is influenced primarily by changes in liver blood flow rather than by changes in the intrinsic clearance, i.e., the metabolizing enzymatic activity.
Pharmacokinetics
12.3 Pharmacokinetics Following a single 5 mg dose of asenapine, the mean C max was approximately 4 ng/mL and was observed at a mean t max of 1 hour. Elimination of asenapine is primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs. With multiple-dose twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics. Absorption: Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Increasing the dose from 5 mg to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration. The absolute bioavailability of asenapine when swallowed is low (<2% with an oral tablet formulation). The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration [see Dosage and Administration ] . Distribution: Asenapine is rapidly distributed and has a large volume of distribution (approximately 20 to 25 L/kg), indicating extensive extravascular distribution. Asenapine i