Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX13 
TREVICTA contains a racemic mixture of (+)- and (-)-paliperidone.

Mechanism of action
Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alpha 1-adrenergic receptors and slightly less, H1-histaminergic and alpha 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.

Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the symptoms of schizophrenia, it causes less catalepsy and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.



Clinical efficacy

The efficacy of TREVICTA in the maintenance treatment of schizophrenia in subjects who have been adequately treated for at least four months with 1-monthly paliperidone palmitate injectable and the last two doses of the same dosage strength was evaluated in one long-term randomised withdrawal double-blind, placebo-controlled study and one long-term double-blind, active-controlled, non-inferiority study. For both studies, the primary outcome was based on relapse.

In the long-term randomised withdrawal study, 506 adult subjects who met DSM-IV criteria for schizophrenia were enrolled into the open-label transition phase and treated with flexible doses of 1-monthly paliperidone palmitate injectable administered into the deltoid or gluteal muscle (50-150 mg) for 17 weeks (dose adjustments occurred at weeks 5 and 9). A total of 379 subjects then received a single dose of TREVICTA in either the deltoid or gluteal muscle in the open-label stabilisation phase (dose was a 3.5 multiple of the last dose of 1-monthly paliperidone palmitate).
Subjects who were considered clinically stable at the end of the 12-week stabilisation phase were then randomised 1:1 to TREVICTA or placebo in a variable duration double-blind phase (the dose of TREVICTA was the same as the last dose received during the stabilisation phase; this dose remained fixed throughout the double-blind phase). In this period, 305 symptomatically stable subjects were randomised to continue treatment with TREVICTA (n = 160) or placebo (n = 145) until relapse, early withdrawal, or the end of study. The primary efficacy variable was time to first relapse. The study was terminated on the basis of a pre-planned interim analysis conducted when 283 subjects had been randomised and 42 relapse events had been observed.
Based on the final analysis (N = 305), 42 subjects (29.0%) in the placebo group and 14 subjects (8.8%) in the TREVICTA group had experienced a relapse event during the double blind phase.The hazard ratio was 3.81 (95% CI: 2.08, 6.99 indicating a 74% decrease in relapse risk with TREVICTA compared to placebo. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1.
There was a significant difference (p < 0.0001) between the two treatment groups in the time to relapse in favour of TREVICTA. The time to relapse of the placebo group (median 395 days) was significantly shorter than for the TREVICTA group (the median could not be estimated due to the low percentage of subjects with relapse [8.8%]).


100
Estimated Percent of Subjects Without Relapse


80



60



40

TREVICTA (N=160)     logrank test, p-value<0.0001

20
Placebo (N=145)


0
28     56   84   112   140    168   196   224   252   280     308   336   364    392   420   448 
Time(days) since Randomization

Figure 1: Kaplan-Meier plot of time to relapse – Final analysis
In the non-inferiority study, 1,429 acutely ill subjects (baseline mean PANSS total score: 85.7) who met DSM-IV criteria for schizophrenia were enrolled into the open-label phase and treated with 1-monthly paliperidone palmitate injectable for 17 weeks. The dose could be adjusted (i.e., 50 mg, 75 mg, 100 mg, or 150 mg) at the week 5 and 9 injections and the injection site could be deltoid or gluteal. For subjects that met randomisation criteria at weeks 14 and 17, 1,016 were randomised in a 1:1 ratio to continue on monthly injections of 1-monthly paliperidone palmitate injectable or to switch to TREVICTA with a 3.5 multiple of the week 9 and 13 dose of 1-monthly paliperidone palmitate injectable for 48 weeks. Subjects received TREVICTA once every 3 months and received placebo-injectable medication for the other months to maintain the blind. The primary efficacy endpoint of the study was the percentage of subjects who had not relapsed at the end of the 48-week double-blind phase based on the Kaplan-Meier 48-week estimate (TREVICTA: 91.2%, 1-monthly paliperidone palmitate injectable: 90.0%). The median time to relapse in either group could not be estimated due to low percentage of subjects with relapse. The difference (95% CI) between the treatment groups was 1.2% (-2.7%, 5.1%), meeting non-inferiority criterion based on a margin of -10%. Thus, the TREVICTA treatment group was non-inferior to 1-monthly paliperidone palmitate injectable. Improvements in functioning, as measured by the Personal and Social Performance scale (PSP), which was observed during the open-label stabilisation phase were maintained during the double-blind phase for both treatment groups.



Figure 2: Kaplan-Meier plot of time to relapse comparing TREVICTA and 1-monthly paliperidone palmitate injectable

The efficacy results were consistent across population subgroups (gender, age, and race) in both studies.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with TREVICTA in all subsets of the paediatric population in schizophrenia. See section 4.2 for information on paediatric use.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption and distribution
Due to its extremely low water solubility, the 3-monthly formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolysed to paliperidone and absorbed into the systemic circulation. The release of the active substance starts as early as day 1 and lasts for as long as 18 months.

The data presented in this paragraph are based on a population pharmacokinetic analysis. Following a single intramuscular dose of TREVICTA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 30-33 days. Following intramuscular injection of TREVICTA at doses of 175-525 mg in the deltoid muscle, on average, an 11-12% higher Cmax was observed compared with injection in the gluteal muscle. The release profile and dosing regimen of TREVICTA results in sustained therapeutic concentrations. The total exposure of paliperidone following TREVICTA administration was dose-proportional over a 175-525 mg dose range, and approximately dose-proportional for Cmax. The mean steady-state peak:trough ratio for a TREVICTA dose was 1.6 following gluteal administration and 1.7 following deltoid administration.

The plasma protein binding of racemic paliperidone is 74%.

Following administration of TREVICTA, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.7-1.8.

Biotransformation and elimination

In a study with oral immediate release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolised in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the faeces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.

In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Based on population pharmacokinetic analysis, the median apparent half-life of paliperidone following TREVICTA administration over the dose range of 175-525 mg ranged from 84-95 days following deltoid injections and 118-139 days following gluteal injections.

Long-acting 3-monthly paliperidone palmitate injection versus other paliperidone formulations 
TREVICTA is designed to deliver paliperidone over a 3-month period, while 1-monthly paliperidone palmitate injection is administered on a monthly basis. TREVICTA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-monthly paliperidone palmitate injection (see section 4.2), results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-monthly paliperidone palmitate injection and corresponding once daily doses of paliperidone extended release tablets. The exposure range for TREVICTA is encompassed within the exposure range for the approved dose strengths of paliperidone extended release tablets.

Hepatic impairment

Paliperidone is not extensively metabolised in the liver. Although TREVICTA was not studied in patients with hepatic impairment, no dose adjustment is required in patients with mild or moderate hepatic impairment. In a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. Paliperidone has not been studied in patients with severe hepatic impairment.

Renal impairment

TREVICTA has not been systematically studied in patients with renal impairment. The disposition of a single oral dose of a paliperidone 3 mg extended release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min), and 71% in severe (CrCl = 10 to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5, 2.6, and 4.8-fold, respectively, compared to healthy subjects.

Elderly

Population pharmacokinetics analysis showed no evidence of age related pharmacokinetics differences.

Body mass index (BMI)/body weight

Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with TREVICTA, the trough concentrations were similar among normal, overweight, and obese subjects.

Race

Population pharmacokinetics analysis showed no evidence of race related pharmacokinetics differences.

Gender

Population pharmacokinetics analysis showed no evidence of gender related pharmacokinetics differences.

Smoking status

Based on in vitro studies utilising human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. Effect of smoking on the pharmacokinetics of paliperidone was not studied with TREVICTA. A population pharmacokinetic analysis based on data with oral paliperidone extended release tablets showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is not likely to be of clinical relevance.