P.3.d.008 Asenapine pharmacokinetics: influence of cytochrome p450 modulators and udp-glucuronyltransferase inhibition

Dogterom, Peter; Hulskotte, Ellen; Gerrits, Mireille; Timmer, C. J.; Sitsen, J. M. A.; Greef, H. De; Spaans, Edwin; Peeters, Pierre

doi:10.1016/s0924-977x(08)70669-2

Cited by 6 publications

(12 citation statements)

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“…Peak asenapine plasma concentrations of approximately 4 ng/mL are reached approximately 1 hour after sublingual dosing. 10 The administration of a strong CYP1A2 inhibitor, such as fluvoxamine, or severe hepatic impairment has been reported to increase asenapine exposure 11,12 ; exposure to asenapine is not altered in a clinically relevant manner by renal impairment or by mild to moderate hepatic impairment. 11 The asenapine schizophrenia clinical trials program has compared asenapine to placebo, with different agents being used as active comparators (ie, olanzapine, risperidone, and haloperidol).…”

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confidence: 99%

Efficacy and Safety of Asenapine in a Placebo- and Haloperidol-Controlled Trial in Patients With Acute Exacerbation of Schizophrenia

Kane¹,

Cohen²,

Zhao³

et al. 2010

Journal of Clinical Psychopharmacology

114

118

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Asenapine is approved by the Food and Drugs Administration in adults for acute treatment of schizophrenia or of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. In a double-blind 6-week trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine at 5 mg twice daily (BID), asenapine at 10 mg BID, placebo, or haloperidol at 4 mg BID (to verify assay sensitivity). With last observations carried forward (LOCF), mean Positive and Negative Syndrome Scale total score reductions from baseline to endpoint were significantly greater with asenapine at 5 mg BID (-16.2) and haloperidol (-15.4) than placebo (-10.7; both P < 0.05); using mixed model for repeated measures (MMRM), changes at day 42 were significantly greater with asenapine at 5 and 10 mg BID (-21.3 and -19.4, respectively) and haloperidol (-20.0) than placebo (-14.6; all P < 0.05). On the Positive and Negative Syndrome Scale positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine at 5 mg BID was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM. Treatment-related adverse events (AEs) occurred in 44% and 52%, 57%, and 41% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Extrapyramidal symptoms reported as AEs occurred in 15% and 18%, 34%, and 10% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Across all groups, no more than 5% of patients had clinically significant weight change. Post hoc analyses indicated that efficacy was similar with asenapine and haloperidol; greater contrasts were seen in AEs, especially extrapyramidal symptoms.

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confidence: 99%

Efficacy and Safety of Asenapine in a Placebo- and Haloperidol-Controlled Trial in Patients With Acute Exacerbation of Schizophrenia

Kane¹,

Cohen²,

Zhao³

et al. 2010

Journal of Clinical Psychopharmacology

114

118

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“…Data on the pharmacokinetic properties of asenapine are available from several studies in healthy volunteers, [22][23][24][25] or patients with hepatic or renal impairment; [26] all of which are published as abstracts.…”

Section: Pharmacokinetic Profilementioning

confidence: 99%

“…[22,24] Asenapine is extensively metabolized, predominantly by uridine diphosphate-glucuronyltransferase (UGT) and cytochrome P450 (CYP) isoenzymes, with asenapine N-glucuronide and N-desmethylasenapine being two major metabolites. [22,25] Both of these metabolites are largely inactive. [22,25] Following administration of single-dose sublingual asenapine 5 mg in healthy volunteers, the C max values for asenapine N-glucuronide and N-desmethylasenapine were 5.34 and 0.39 ng/mL, respectively.…”

Section: Pharmacokinetic Profilementioning

confidence: 99%

“…[22,25] Both of these metabolites are largely inactive. [22,25] Following administration of single-dose sublingual asenapine 5 mg in healthy volunteers, the C max values for asenapine N-glucuronide and N-desmethylasenapine were 5.34 and 0.39 ng/mL, respectively. [22] Corresponding AUC ¥ values were 72.3 and 9.52 ng Á h/mL.…”

Section: Pharmacokinetic Profilementioning

confidence: 99%

“…[25] Concomitant administration of the CYP modulators cimetidine (nonspecific CYP inhibitor), carbamazepine (CYP3A4 inducer) and paroxetine (CYP2D6 inhibitor/substrate) produced only minor alterations in asenapine exposure that were not considered clinically relevant (AUC ¥ values increased by up to 1% or decreased by up to 16%). [23,25] However, concomitant administration of the CYP1A2 inhibitor fluvoxamine increased the AUC ¥ of asenapine by 29%. [25] In vivo, asenapine is a weak inhibitor of CYP2D6.…”

Section: Pharmacokinetic Profilementioning

confidence: 99%

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Asenapine

Weber

McCormack

2009

CNS Drugs

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Asenapine is a novel psychopharmacological agent that binds with high affinity and specificity to numerous dopamine, serotonin, noradrenaline (norepinephrine) and histamine receptor subtypes. It is being developed for the treatment of schizophrenia and bipolar mania. In two randomized, controlled trials of asenapine monotherapy and in one randomized, controlled trial of adjunctive asenapine therapy in adult patients with bipolar I disorder, sublingual asenapine produced significantly greater reductions from baseline than placebo in clinician-assessed Young Mania Rating Scale (YMRS) total score at 3 weeks. In two randomized, controlled trials in adult patients with acute schizophrenia, treatment with asenapine reduced from baseline the clinician-assessed Positive and Negative Syndrome Scale (PANSS) total score to a significantly greater extent than placebo at 6 weeks. In schizophrenic patients with predominant, persistent, negative symptoms, asenapine at 26 weeks reduced the Negative Symptom Assessment (NSA-16) total score from baseline to an extent similar to that observed with olanzapine. Sublingual asenapine was generally well tolerated in clinical trials, with most treatment-emergent adverse events being of mild to moderate severity. Incidence rates of clinically significant weight gain, extrapyramidal symptoms, hyperprolactinaemia and alterations in glucose or lipid metabolism were generally low.

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A 3‐week, randomized, placebo‐controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

McIntyre

Cohen²,

Zhao³

et al. 2009

Bipolar Disorders

160

204

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P.3.d.008 Asenapine pharmacokinetics: influence of cytochrome p450 modulators and udp-glucuronyltransferase inhibition

Cited by 6 publications

References 0 publications

Efficacy and Safety of Asenapine in a Placebo- and Haloperidol-Controlled Trial in Patients With Acute Exacerbation of Schizophrenia

Efficacy and Safety of Asenapine in a Placebo- and Haloperidol-Controlled Trial in Patients With Acute Exacerbation of Schizophrenia

Asenapine

A 3‐week, randomized, placebo‐controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

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