Asenapine, Iloperidone and Lurasidone

Critical Appraisal of the Most Recently Approved Pharmacotherapies for Schizophrenia in Adults

William V Bobo


Expert Rev Clin Pharmacol. 2013;6(1):61-91. 

In This Article

Pharmacological Profile


Iloperidone exhibits high affinity for dopamine D2 and D3, and serotonin 5-HT2A receptors, where they act as antagonists (Table 1),[17–19] a pattern consistent with its atypical antipsychotic profile; however, the functional significance of iloperidone's antagonist activity at dopamine D3 receptors is unknown. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and noradrenergic α1 receptors; and with low affinity to dopamine D1, serotonin 5-HT1A and histamine H1 receptors.[17,18] Iloperidone has no significant binding activity at muscarinic cholinergic M1 receptors.[18] Iloperidone functions as an antagonist at noradrenergic α1 receptors, which predicts its orthostatic hypotensive effects.[17,18]

Asenapine, like most other atypical antipsychotics, is also a potent antagonist at dopamine D2 and serotonin 5-HT2A receptors (Table 1).[17,20] Asenapine also binds potently to serotonin 5-HT1A, 5-HT2C, 5-HT6, 5-HT7, histamine H1 and noradrenergic α1 receptors, but has negligible affinity for muscarinic M1 receptors.[17,20,201] With the exception of muscarinic M1 receptors, asenapine behaves as a potent antagonist at each of these sites.[21] There is evidence that asenapine acts as a partial agonist at 5-HT1A receptors.[22] Interestingly, weight gain with asenapine during short- and long-term clinical studies has been modest despite its potent serotonin 5-HT2C and histamine H1 receptor antagonist profile (reviewed below).[23,24] In addition, clinical studies of asenapine document a low incidence of orthostatic hypotension and dizziness despite asenapine's potent antagonist effects at noradrenergic α1 receptors.[25]

Lurasidone also binds with high affinity to dopamine D2 and serotonin 5-HT2A receptors, and to 5-HT7 receptors (Table 1).[26] As shown in Table 1, lurasidone binds with marginally higher affinity to D2 than 5-HT2A receptors. Lurasidone has moderate binding affinity for serotonin 5-HT1A receptors; weak affinity for noradrenergic α1 and α2c, and serotonin 5-HT2C receptors; and no significant binding activity at histamine H1 or muscarinic M1 receptors.[26] Lurasidone acts as an antagonist at D2 and serotonin 5-HT2A and 5-HT7 receptors, and a partial agonist at serotonin 5-HT1A receptors.[26]

Pharmacokinetics & Metabolism

Iloperidone is formulated as solid tablets for oral administration, the available milligram strengths are listed in Table 2 .[202] Iloperidone is well absorbed from the GI tract and peak plasma concentrations are reached within 2–4 hours.[202] Administration with food has no significant effect on the area under the curve, tmax or Cmax.[27] Steady-state concentration is reached within 3–4 days of initial dosing.[202] Iloperidone is ~95% protein bound, and is extensively metabolized in the liver via CYP2D6 and CYP3A4.[28] The mean elimination half-life of iloperidone is 18 hours for CYP2D6 extensive metabolizers, and 33 hours for slow metabolizers.[202] One of iloperidone's two primary metabolites (P88–8991) has a receptor binding profile similar to that of the parent compound, while the other (P95-12113) does not appear to cross the blood–brain barrier to a significant degree.[29]

Asenapine is formulated as a rapidly dissolving tablet for sublingual or buccal administration ( Table 2 ).[203] Thus, the primary site of drug absorption is the oral mucosa, which results in a bioavailability of approximately 35%. Swallowing the tablet reduces bioavailability to <2%. Asenapine is rapidly absorbed, and reaches peak plasma concentration within 0.5–1.5 hours.[203] However, drinking liquids within 10 minutes of sublingual administration of asenapine can significantly reduce its bioavailability; thus, avoidance of eating or drinking within 10 minutes of asenapine administration is recommended.[203] Steady-state concentrations are reached within 3 days if administered twice daily (b.i.d.). Asenapine is highly (95%) protein bound, undergoes direct glucuronidation by UGT1A4 and is metabolized in the liver by the CYP1A2 isoenzyme (to a lesser degree by CYP3A4, followed by CYP2D6).[30,203] Asenapine is converted to several metabolites,[30] none of which are thought to contribute significantly to its overall pharmacological profile. The mean elimination half-life of asenapine is 13–39 hours. Severe hepatic impairment (Child–Pugh class C), but not mild to moderate impairment (Child–Pugh classes A or B, respectively), results in profound increases in asenapine concentration, while no degree of renal impairment appears to result in increased asenapine exposure.[31] As such, the product label recommends against the use of asenapine for patients with severe hepatic impairment, while no adjustment of dose appears warranted based on renal function.[203]

Lurasidone is formulated as a solid oral tablet and is rapidly absorbed, reaching peak plasma concentration in 1–3 hours.[204] The absorption of lurasidone is significantly increased when administered with food: area under the curve and Cmax are increased two- and three-fold, respectively, in the fed versus fasting state.[204] Lurasidone is distributed widely throughout the body, is highly (99.8%) protein bound and extensively metabolized in the liver via the CYP3A4 isoenzyme.[204] Lurasidone has three pharmacologically active metabolites, one of which (ID-14283) has a pharmacodynamic profile similar to that of the parent compound.[32] The mean elimination half-life of lurasidone is 18 hours, but may be expected to be higher after achieving steady-state concentrations.[33]

Drug Interactions & Dosing

The recommended starting doses, dose titration schedules and usual clinical dose ranges are presented in Table 2.

Iloperidone Even though the clinically effective dose range of iloperidone for treating adults with schizophrenia is 6–12 mg b.i.d., the recommended starting dose is low (1 mg b.i.d.) and titration is required in order to lower orthostatic hypotension risk.[202] As specified in the product labeling, adequate symptom control may be slightly delayed compared with agents that do not require titration to clinically effective doses.[204] Strong inhibitors of CYP2D6 (i.e., fluoxetine, paroxetine, and so on) or CYP3A4 (i.e., ketoconazole, clarithromycin, and so on) can significantly delay the metabolism and elimination of iloperidone, leading to elevated iloperidone blood levels (Table 2).[202] Thus, the total daily dose of iloperidone will need to be reduced (by 50%, according to the manufacturing label) if used in the presence of strong CYP2D6 and 3A4 inhibitors.[202] Coadministering iloperidone with other QT-prolonging drugs should be avoided (Table 2).[202] Iloperidone is not recommended for use in patients with hepatic impairment. Because renal impairment and smoking status are unlikely to significantly alter drug levels in absence of other pharmacokinetic factors,[28,202] dosage adjustment is not likely to be required.

Asenapine The recommended starting dose for asenapine is 5 mg b.i.d., with an effective dose range of 5–10 mg b.i.d..[203] As noted above, asenapine is formulated for sublingual use. Thus, the tablets should not be split to allow for single doses under 5 mg, nor should they be crushed, chewed or swallowed. The risk of clinically significant drug–drug interactions involving asenapine has not been extensively evaluated. Caution is advised when administering asenapine with CYP1A2 inhibitors (i.e., fluvoxamine, and so on), which may significantly increase asenapine exposure.[203] Asenapine is a weak CYP2D6 inhibitor, and may increase exposure to drugs that are CYP2D6 substrates (such as paroxetine). Thus, caution is also advised when combining asenapine with other drugs that act as both substrates and inhibitors for CYP2D6 (Table 2).[203] Because asenapine acts as a potent noradrenergic α1 receptor antagonist,[17] blood pressure and orthostatic symptom monitoring may be required when combining asenapine with antihypertensive drugs, particularly those with anti-adrenergic properties (Table 2). Asenapine is not recommended for use in patients with severe hepatic impairment (Child–Pugh class C), while dosage adjustment is not required based solely on level of renal impairment.[31] Smoking has not been shown to significantly alter asenapine exposure.[34]

Lurasidone The recommended starting dose of lurasidone is 40 mg daily, and recent changes to product labeling reflect an expanded effective dose range of 40–160 mg daily.[204] All lurasidone doses should be taken with food (>350 calories), as also reflected in the current product labeling.[204] Caution is recommended when coadministering lurasidone with moderate CYP3A4 inhibitors, with an upper dose limit of 40 mg/day (Table 2).[204] Combining lurasidone with potent CYP3A4 inducers (i.e., rifampin, and so on) or inhibitors (i.e., diltiazepin, and so on) is contraindicated, as these interactions can significantly alter exposure to lurasidone (Table 2).[204] The manufacturer has recommended against prescribing lurasidone at doses above 40 mg daily in patients with moderate or severe hepatic impairment, or with severe renal impairment.[204] Because lurasidone is not a CYP1A2 substrate, smoking is not expected to alter drug levels in absence of other pharmacokinetic factors.