Eur J Clin Pharmacol (2015) 71:65–74 DOI 10.1007/s00228-013-1587-4

PHARMACOKINETICS AND DISPOSITION

The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers Peter Dogterom & Rik de Greef & Pierre A. M. Peeters

Received: 5 June 2013 / Accepted: 9 September 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose To determine the effects of food on the pharmacokinetics of sublingual asenapine. Methods Healthy male volunteers (n =26, age 19–53 years) randomly received a single sublingual dose of asenapine 5 mg after ≥10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after ≥10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis. Results Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-∞) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h postdose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration– time profiles for both food regimens. Conclusions To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of P. Dogterom (*) : P. A. M. Peeters Early Stage Development, Merck Sharp & Dohme, PO Box 20, 5340 BH Oss, The Netherlands e-mail: [email protected] R. de Greef Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme, Oss, The Netherlands Present Address: P. A. M. Peeters Centre for Human Drug Research, Leiden, The Netherlands

a drug. A high-fat meal taken before or 4 h post-dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing. Keywords Asenapine . Pharmacokinetics . Food effect . Healthy subjects

Introduction Asenapine is a novel antipsychotic that has been recently introduced onto the market. In the USA, asenapine is indicated for acute treatment of adults with schizophrenia and as monotherapy or adjunctive therapy in the treatment of manic or mixed episodes associated with bipolar I disorder in adults with or without psychotic features [1]. Asenapine is also approved in the European Union for the treatment of moderate to severe manic episodes associated with bipolar I disorder [2]. The human receptor signature of asenapine is characterized by a high affinity for serotonergic (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, 5-HT7), α-adrenergic (α1, α2A, α2B, α2C), dopaminergic (D1, D2, D3, D4) and histaminic (H1, H2) receptors but a minimal affinity for muscarinic receptors; its affinity is higher for the 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7, α2B and D3 receptors than for D2 receptors [3]. Among the array of antipsychotics that are currently available, asenapine is the only drug that is available as a sublingual formulation. Although the clinical development of asenapine initially started as a conventional oral tablet formulation, this was soon discontinued because of unexpected low bioavailability (