title: Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data.
abstract: Paliperidone palmitate is a second-generation, long-acting injectable (LAI) antipsychotic recently approved by the US FDA and European Medicines Agency for use in patients with schizophrenia. This article reviews the recommended dosing regimens for initiation and maintenance treatment with paliperidone palmitate in adult patients with schizophrenia. We also address issues of switching to paliperidone palmitate from other antipsychotics, managing missed doses and dosing in special patient populations. The dosing recommendations that were approved by the FDA and other regulatory agencies around the world are based on the results of population pharmacokinetic (PK) simulations and data from clinical trials that are presented in this review. A one-compartment disposition model with zero/first-order absorption best described the PK of paliperidone palmitate. Population PK models for extended-release paliperidone and long-acting risperidone were also developed and we report the results from these models. The PK profiles for 5000 patients were simulated after paliperidone palmitate injections. The population median and 90% prediction intervals of the simulated plasma concentration versus time profiles after multiple doses are graphically displayed in this review. Based on the data from model-based PK simulations, the approved recommended initiation regimen for paliperidone palmitate is 150 mg equivalent (mg eq.) paliperidone (paliperidone palmitate 234 mg) on day 1 followed by 100 mg eq. paliperidone (paliperidone palmitate 156 mg) on day 8, each administered into the deltoid muscle, using a 1-inch 23-gauge needle in those weighing <90 kg and a 1.5-inch 22-gauge needle in those weighing ≥90 kg. No oral supplementation is required. Monthly maintenance dosing is in the range of 25-150 mg eq. paliperidone (paliperidone palmitate 39-234 mg; recommended dose of 75 mg eq. paliperidone [paliperidone palmitate 117 mg]) injected into the deltoid (needle size is weight adjusted) or gluteal (using a 1.5-inch 22-gauge needle) muscle. The day 8 dose may be administered ±2 days and monthly doses ±7 days, without a clinically significant impact on plasma concentrations. The re-initiation schedule in patients whose last maintenance dose was >6 weeks previously is dependent upon the duration of time since the last paliperidone palmitate injection. In patients with mild renal impairment (creatinine clearance [CL(CR)]: 50-80 mL/min), dosage should be adjusted. No dose adjustment is required in patients with mild or moderate hepatic impairment; no data currently exist regarding severe hepatic impairment. Elderly patients with normal renal function should receive the same dosage as younger adult patients with normal renal function. In the event of an age-related decline in CL(CR), dosage should be adjusted accordingly. Paliperidone palmitate can be initiated the day after discontinuing previous oral antipsychotic treatment. In patients switching from other LAIs (including long-acting risperidone), paliperidone palmitate dosing should be initiated at the time of what would have been the next scheduled injection of the previous LAI, and continued monthly thereafter. In summary, following initiation dosing, paliperidone palmitate is administered on a monthly basis. It is the first of the second-generation antipsychotics to be available and approved with this dosing regimen. Population PK modelling presented in this review has helped provide practical guidance for administering this novel LAI antipsychotic.
authors.affiliation: Johnson Johnson Pharmaceutical Research Development, L.L.C., Raritan, NJ, USA. MSamtani@its.jnj.com
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.forename: Srihari
authors.initials: S
authors.lastname: Gopal
authors.forename: Cristiana
authors.initials: C
authors.lastname: Gassmann-Mayer
authors.forename: Larry
authors.initials: L
authors.lastname: Alphs
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Palumbo
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D006801:Humans; D007273:Injections, Intramuscular; D007555:Isoxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D010168:Palmitates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D010168:Palmitates; D000068882:Paliperidone Palmitate