ase in Cmax (13.7 to 28.9 ng/mL) and 2-fold increase in AUCtau (5706 to 11658 ng*hr/mL). For total active moiety, a 2-fold increase in dose resulted in a 2.0-fold increase in Cmax (19.6 to 38.5 ng/mL) and a 1.9-fold increase in AUCtau (8102 to 15370 ng*hr/mL).
Plasma exposures at steady-state were compared between oral risperidone and PERSERIS. Based on average plasma concentrations (Cavg) of risperidone and total active moiety, 90 mg PERSERIS corresponds to 3 mg oral risperidone and 120 mg PERSERIS corresponds to 4 mg oral risperidone.
Absorption
PERSERIS contains risperidone in a liquid delivery system. Following subcutaneous injection, it forms a depot that provides sustained plasma levels of risperidone over the monthly dosing interval.
After single subcutaneous injection, PERSERIS shows two absorption peaks for risperidone in plasma. The first peak of risperidone occurs with a Tmax of 4 to 6 hours and is due to an initial release of the drug during the depot formation process. A second peak of risperidone is observed at 10 to 14 days post-dose and is associated with the slow release of risperidone from the subcutaneous depot. The first and second peaks of risperidone are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median Tmax of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days.
Distribution
Following a subcutaneous injection of PERSERIS, the apparent volume of distribution is large. The extensively large values are because PERSERIS is administered as a depot injection. Risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displace each other from plasma binding sites.
Elimination
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme cytochrome CYP2D6 with minor contribution by CYP3A4. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone).
CYP2D6, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly. Plasma exposure to total active moiety was similar in CYP2D6 extensive, intermediate and poor metabolizers following subcutaneous injection with PERSERIS, supporting no need for dose adjustment based on genotype of CYP2D6.
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to 3 healthy male volunteers, total recovery of radioactivity at 1week was 84%, including 70% in the urine and 14% in the fece |
