Asenapine Pharmacokinetics in Hepatic and Renal Impairment

Background and Objective: The effects of hepatic or renal impairment on the pharmacokinetics of atypical antipsychotics are not well understood. Drug exposure may increase in patients with hepatic disease, owing to a reduction of certain metabolic enzymes. The objective of the present study was to study the effects of hepatic or renal impairment on the pharmacokinetics of asenapine and its N-desmethyl and N ⁺-glucuronide metabolites.

Methods: Two clinical studies were performed to assess exposure to asenapine, desmethylasenapine and asenapine N ⁺-glucuronide in subjects with hepatic or renal impairment. Pharmacokinetic parameters were determined from plasma concentration-time data, using standard noncompartmental methods. The pharmacokinetic variables that were studied included the maximum plasma concentration (C_max) and the time to reach the maximum plasma concentration (t_max). Eligible subjects, from inpatient and outpatient clinics, were aged ≥18 years with a body mass index of ≥18kg/m² and ≤32kg/m². Sublingual asenapine (Saphris®) was administered as a single 5 mg dose.

Asenapine and N-desmethylasenapine exposures were unaltered in subjects with mild or moderate hepatic impairment, compared with healthy controls. Severe hepatic impairment was associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC_∞) values for total asenapine, N-desmethylasenapine and asenapine N ⁺-glucuronide (5-, 3-, and 2-fold, respectively), with slight increases in the C_max of asenapine but 3- and 2-fold decreases in the C_max values for N-desmethylasenapine and asenapine N ⁺-glucuronide, respectively, compared with healthy controls. The mean AUC_∞ of unbound asenapine was more than 7-fold higher in subjects with severe hepatic impairment than in healthy controls. Mild renal impairment was associated with slight elevations in the AUC_∞ of asenapine compared with healthy controls; alterations observed with moderate and severe renal impairment were marginal. N-desmethylasenapine exposure was only slightly altered by renal impairment. No correlations were observed between exposure and creatinine clearance.