title: Drug-Drug Interaction Studies of Paliperidone and Divalproex Sodium Extended-Release Tablets in Healthy Participants and Patients with Psychiatric Disorders.
abstract: The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified.
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Remmerie
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Jay
authors.initials: J
authors.lastname: Ariyawansa
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: De Meulder
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Joris
authors.initials: J
authors.lastname: Berwaerts
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000008:administration & dosage / Q000097:blood*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000097:blood* / Q000188:drug therapy*; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000097:blood*; D013607:Tablets; D014635:Valproic Acid / Q000008:administration & dosage / Q000097:blood*
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D013607:Tablets; D014635:Valproic Acid; D000068882:Paliperidone Palmitate
keywords: bioavailability; paliperidone extended release; pharmacokinetics; phase 1; valproic acid