This is the first study to examine the long-term pharmacokinetics and tolerability of the highest available dose of PP (150 mg eq.) as fixed dose injections in patients with schizophrenia. Shorter-term fixed-dose studies have shown that PP at doses of 25, 50, 75, 100, or 150 mg eq. was efficacious and tolerable in the treatment of schizophrenia [10
]. Especially as some dose-related effects were observed in these previous studies, it was important to determine if long-term treatment with the maximum available dose was safe and tolerable. In this 1-year phase-1 study of PP in stable patients with schizophrenia, PP was administered either as fixed doses of the highest available 150 mg eq. dose or as flexible doses up to 150 mg eq.). Despite the option for down titration in the flexible-dose group, the majority of patients remained in the fixed dose group, and of the 26 patients opting for flexible dosing, 7 continued on 150 mg eq. dosing. That more than half of the patients completed the trial, and that the majority of those continued on 150 mg eq for the duration of the study attests to the tolerability of the highest available dose during long-term therapy. The results indicate that the safety and tolerability profile of long-term maintenance dosing with PP 150 mg eq. is consistent with that shown in previous short-term studies that included this dose [22
] as well as with studies across the dose range [10
] and no new safety signals emerged. The overall incidence of TEAEs, and the incidences of serious TEAEs, EPS-related and prolactin-related TEAEs were also high in patients who did not complete the study at 150 mg eq. compared with those who completed the study at the dose of 150 mg eq. of PP.
The recommended monthly maintenance dose of PP is 75 mg eq. (117 mg) [9
], although some patients may benefit from higher or lower doses.
Generally, the incidence of discontinuations in this long-term study (47%) is consistent with rates observed in previous short duration PP studies [23
] and also with rates reported in other drug studies in schizophrenia [26
]. In the current study, patients were exposed to PP 150 mg eq. for a mean duration of 250 days, and approximately half the patients completed the study.
Attainment of optimal therapeutic plasma concentration is important while starting treatment with a LAI [5
]. In this study, a median plasma paliperidone concentration of above 7.5 ng/mL, which is associated with a central D2-receptor occupancy of approximately 60% [28
], was reached within 2 to 4 days after the first dose. This is within the range (60-80%) associated with antipsychotic efficacy [29
]. This also confirms that the 150 mg eq. initiation dose administered in the deltoid muscle (using a weight-adjusted needle length) resulted in rapid attainment of target plasma paliperidone concentrations. Steady-state plasma concentrations of paliperidone were reached after approximately 8 to 9 months and the plasma concentrations were within the predicted range by the population PK model. The median concentrations profile of paliperidone during the first 3 months was consistent with those from a previous phase-3 study [23
The study also allowed an opportunity to look at how the PK results were impacted by ethnicity, given the diversity of demographic characteristics of the study population, with enrollment of a large number of Asian participants. The population PK analyses of this data revealed that, Asian patients had higher plasma exposure to paliperidone than White patients; this could be attributed to the lower BMI in Asians. However, across studies, it has been found that BMI rather than ethnicity, has the most impact on the PK of PP, but this is overcome by the recommended dosing regimen and use of appropriate needle length [34
Metabolic adverse effects such as dose-related weight gain (≤ 2.6 kg) have been reported in earlier studies with PP [10
]. Consistent with these earlier results, average weight increased (approximately 2.5 kg) in the course of the 1-year study. This weight gain was lower than that observed with other atypical antipsychotics such as olanzapine (4.15 kg over a 10-week treatment period) [35
]. Also consistent with previous data, there were a low proportion of treatment-emergent glucose-related adverse events in the current study, and no clinically relevant changes in lipid profile were noted [10
]. Underlying risk factors were identified for each of the patients with glucose-related adverse events, suggesting that PP was not the primary cause.
Approximately one-fourth of the patients experienced at least one EPS-related TEAE during this study. A majority of the EPS-related TEAEs in this study were nonserious. Most of these incidences occurred during the first month of treatment and the rate subsequently decreased to < 5% throughout. There were only 4 reported discontinuations due to EPS-related events. The EPS scales indicated distinct increases in the rates of parkinsonism (16%), while rates for akathisia and dyskinesia were low (1-2%). The proportion of patients requiring anticholinergic medications at endpoint was consistent to those reported earlier for PP [10
]. Despite long-term treatment with the 150 mg eq. dose in this study, only one case of mild TD was reported in this study. The event resolved on continued PP treatment, making the diagnosis of TD uncertain. This low incidence of TD is consistent with results of a previous 33-week study with PP, where only one incidence of TD was reported at 100 mg eq. dose [21
]. There were no reports of TD in the previous short-term PP schizophrenia studies across dose ranges 25 to 150 mg eq. [10
As expected, increases in prolactin levels were greater in women than in men, consistent with previous data [10
]. However, the incidence of prolactin-related TEAEs was higher in this study than previous phase 3 PP studies, in which the incidence of potentially prolactin-related TEAEs was low (ranging from ≤ 1-2%), consistent with the generally lower doses used and the shorter treatment period of those studies [10
]. The increased prolactin levels in women gradually declined at the end of the study. Importantly, most of the potentially prolactin- related TEAEs observed in this phase-1 study were reported as isolated laboratory abnormalities, and patients were generally asymptomatic with a few exceptions.
There are several limitations to this study. Firstly, this study did not include a placebo group, such that no background rates of TEAE incidences were available for comparison. This limits the clinical interpretation of the data. Also, this study was designed as a safety study and efficacy measurements were secondary objectives. Because the patients enrolled in this study were symptomatically stable, the efficacy results cannot be extrapolated to patients with acute schizophrenia. Though efficacy was not the primary objective of the study, patients generally remained stable both symptomatically and functionally throughout the study. As the average age of patients was between 25-50 years and no elderly patients were included, these results cannot be generalized to either a pediatric or geriatric population. Hyperprolactinemia is a common adverse effect associated with antipsychotic agents. For patients with elevated prolactin concentrations, the practitioners are apt to query for presence of clinical symptoms related to hyperprolactinemia. No specific queries for prolactin-related adverse events were required as per the study protocol. Depending upon the nature of such events and the doctor-patient relationship, patients may or may not be forthcoming in reporting them. Hence, it is possible that prolactin-related adverse events have been underreported.