Abstract
BackgroundThere are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period.MethodsIn this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B.ResultsOf the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable.ConclusionsSafety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range.Trial registration noClinicalTrials.gov: NCT01150448
Highlights
There are no previous reports of paliperidone palmitate’s (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia
Main exclusion criteria included: primary active Diagnostic and Statistical Manual of Mental Disorders (DSMIV) Axis I diagnosis other than schizophrenia, involuntary commitment to psychiatric hospitalization, previous treatment with injectable antipsychotic formulations other than PP or risperidone-long-acting injectable (LAI)) within 1 injection interval on day 1, previous PP injection within 10 months or risperidone-LAI injection within 100 days before day 1, at significant risk of suicidal or violent behavior, history of neuroleptic malignant syndrome or tardive dyskinesia (TD), hypersensitivity to risperidone, paliperidone or their excipients, history of significant or unstable systemic disease, or history or presence of circumstances that would increase the risk of torsade de pointes or sudden death associated with the use of drugs that prolong QT interval
Sample size determination Using an estimated intrapatient coefficient of variation of 40% for AUCτ and Cmax of paliperidone after PP injection, and a 5% significance level, a sample size of 40 patients from Treatment A was considered sufficient for the point estimate of the relative bioavailability after the 8th i.m. injection of PP 150 mg eq compared to the 2nd i.m. injection of PP 150 mg eq to fall within 86.0% and 116.3% of the true value, with 90% confidence
Summary
There are no previous reports of paliperidone palmitate’s (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. As compared with the oral formulations, the long-acting injectable (LAI) formulations of antipsychotic drugs have the advantage of a sustained release profile providing therapeutic plasma concentration for several weeks [4], thereby eliminating the need for daily oral medication [5,6,7]. Treatment with PP does not require oral supplementation during initiation, as its pharmacokinetic (PK) profile allows both a rapid achievement of therapeutic plasma levels of paliperidone as well as a gradual and continuous release of the drug over the dosing interval [10]. The approved recommended initiation regimen [9] with deltoid injections of a high dose of PP (150 milligram equivalent [mg eq.]. on day 1 and 100 mg eq on day 8) allows rapid attainment of therapeutic concentrations [11,12]
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