Valproate Reduces the Glucuronidation of Asenapine Without Affecting Asenapine Plasma Concentrations

Asenapine is indicated for treatment of schizophrenia in the United States and acute treatment of manic or mixed episodes, as monotherapy (United States and European Union) or adjunct therapy (United States only), associated with bipolar I disorder. It is extensively metabolized; the 2 main metabolites are asenapine N-glucuronide and N-desmethyl-asenapine. The authors investigated the pharmacokinetic interactions between asenapine and valproate in an open-label, randomized, 2-way crossover study. Twenty-four healthy male volunteers received sublingual doses of asenapine 5 mg alone or under steady-state valproate (500 mg bid for 9 days). Blood samples collected until 72 hours postdosing were analyzed for asenapine, N-desmethyl-asenapine, and asenapine N-glucuronide. Compared with asenapine alone, valproate substantially reduced N-glucuronide formation (area under the curve from 0 to infinity [AUC0−∞] reduced 7.4-fold, maximum concentration [Cmax] reduced 6.6-fold) and moderately reduced N-desmethyl-asenapine formation (AUC0−∞ reduced 30%, Cmax unchanged). Coadministration of valproate did not affect asenapine AUC0−∞ and Cmax (confidence intervals for the ratios of asenapine AUC0−∞ and Cmax were contained within the predefined 0.80-1.25 acceptance range). Low-dose valproate, although almost completely inhibiting glucuronidation of asenapine, did not affect the pharmacokinetics of asenapine itself, the entity primarily responsible for the pharmacologic effects of the drug.