Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3‐month formulation in patients with schizophrenia: A phase‐1, single‐dose, randomized, open‐label study

Abstract

This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18-65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single-dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75-525 mg eq) separated by a washout of 7-21 days. Overall, 245 of 308 (79.5%) PP3M-dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half-life was ∼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment-emergent adverse events. Overall, safety and tolerability were similar to those of the 1-month formulation. Results support a once-every-3-months dosing interval in patients with schizophrenia or schizoaffective disorder.

Prospective dose selection and acceleration of paliperidone palmitate 3‐month formulation development using a pharmacometric bridging strategy

“…PP3M requires at least 4 months of adequate treatment with PP1M to achieve clinical stability, and thereafter, the dose‐multiplier is applied. When a dose multiplier of 3‐ or 3.5‐fold was used between PP1M and PP3M, paliperidone peak concentrations increased only about 2‐fold, and apparent half‐life was prolonged by ≥2‐fold after single dose administration . This allowed PP3M to attain a peak/trough ratio comparable to that observed in the previously developed LAI PP1M and oral paliperidone‐ER formulations.…”

“…The patient populations in the PP3M Phase I and Phase III studies were similar ; the Phase I study included patients with schizophrenia rather than healthy volunteers due to the long‐acting nature of the formulation. In the PP3M Phase I study, all patients were taking antipsychotic medication (but not risperidone or paliperidone), and the PP3M dose was in addition to their existing medication.…”

“…The LAI paliperidone palmitate 3‐month (PP3M), like PP1M, is an aqueous ER suspension. PP3M can be administered just four times a year , and this first‐of‐its‐kind dosing interval is an innovation in schizophrenia treatment. PP3M was approved by the Food and Drug Administration in May 2015 under Priority Review, a designation reserved for “a drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.” In addition, the European Medicines Agency and Health Canada approved PP3M in May 2016 and June 2016, respectively.…”

“…Integrated, lean and adaptive Phase I and III studies of PP3M were undertaken to study single‐ and multiple‐dose pharmacokinetics (PK) . The implementation of learn‐and‐confirm milestones allowed accelerated decision making.…”

Comparison of Gluteal Muscle Intramuscular Injection Sites of Japanese Healthy Subjects: Considerations for Optimal Insertion of Injection Needle Length

“…The phase-1 study assessing the pharmacokinetics, safety, and tolerability of the investigational IM paliperidone palmitate, a 3-month formulation LAI in patients with schizophrenia or schizoaffective disorders has recently been started [30] [31]. More secure techniques, which could complications of injection sites caused by the chemical solution does not reach the muscle, must be developed for such LAI.…”