Chemical formula: C₂₃H₂₇FN₄O₃ Molecular mass: 426.484 g/mol PubChem compound: 115237
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 alfa1-adrenergic receptors and blocks, to a lesser extent, H1-histaminergic and alfa2adrenergic 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 positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions to a lesser extent than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.
The pharmacokinetics of paliperidone are dose proportional within the available dose range.
Following a single dose, paliperidone exhibits a gradual ascending release rate, allowing the plasma concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. With once-daily dosing of paliperidone, steady-state concentrations are attained within 4-5 days of dosing in most subjects.
Paliperidone is the active metabolite of risperidone. The release characteristics of paliperidone result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone (fluctuation index 38% versus 125%).
The absolute oral bioavailability of paliperidone is 28% (90% CI of 23%-33%).
Administration of paliperidone prolonged-release tablets with a standard high-fat/high-caloric meal increases Cmax and AUC of paliperidone by up to 50-60% compared with administration in the fasting state.
Paliperidone palmitate is the palmitate ester prodrug of paliperidone. Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolysed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 13 days. The release of the active substance starts as early as day 1 and lasts for at least 4 months.
Following intramuscular injection of single doses (25-150 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoid intramuscular injections of 150 mg on day 1 and 100 mg on day 8 help attain therapeutic concentrations rapidly. The release profile and dosing regimen of paliperidone results in sustained therapeutic concentrations. The total exposure of paliperidone was dose-proportional over a 25-150 mg dose range, and less than dose-proportional for Cmax for doses exceeding 50 mg. The mean steady-state peak:trough ratio for a paliperidone dose of 100 mg was 1.8 following gluteal administration and 2.2 following deltoid administration. The median apparent half-life of paliperidone over the dose range of 25-150 mg ranged from 25-49 days.
The absolute bioavailability of paliperidone palmitate is 100%.
Following administration of paliperidone palmitate the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6-1.8.
The plasma protein binding of racemic paliperidone is 74%.
Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. The plasma protein binding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin.
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 by 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 6.5% 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 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. The terminal elimination half-life of paliperidone is about 23 hours.
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.
Paliperidone injection is designed to deliver paliperidone over a monthly period while prolonged release oral paliperidone is administered on a daily basis. The initiation regimen for paliperidone injection (150 mg/100 mg in the deltoid muscle on day 1/day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.
In general, overall initiation plasma levels with paliperidone were within the exposure range observed with 6-12 mg prolonged release oral paliperidone. The use of the paliperidone initiation regimen allowed patients to stay in this exposure window of 6-12 mg prolonged release oral paliperidone even on trough pre-dose days (day 8 and day 36). Because of the difference in median pharmacokinetic profiles between the two medicinal products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.
Paliperidone is not extensively metabolised in the liver. Although paliperidone was not studied on 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.
The disposition of a single oral dose paliperidone 3 mg prolonged 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. Based on a limited number of observations with paliperidone in subjects with mild renal impairment and pharmacokinetic simulations, a reduced dose is recommended.
Data from a pharmacokinetic study in elderly subjects (≥65 years of age, n=26) indicated that the apparent steady-state clearance of paliperidone was 20% lower compared to that of adult subjects (18-45 years of age, n=28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction of age-related decreases in CrCl.
Paliperidone systemic exposure in adolescent subjects (15 years and older) was comparable to that in adults. In adolescents weighing <51 kg, a 23% higher exposure was observed than in adolescents weighing ≥51 kg. Age alone did not influence the paliperidone exposure.
Pharmacokinetic studies with paliperidone palmitate have shown somewhat lower (10-20%) plasma concentrations of paliperidone in patients who are overweight or obese in comparison with normal weight patients.
Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone.
The apparent clearance of paliperidone is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and creatinine clearance between men and women.
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. A population pharmacokinetic analysis showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is unlikely to be of clinical relevance, though.
Repeat-dose toxicity studies of intramuscularly injected paliperidone palmitate (the 1-month formulation) and orally administered paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. In animals treated with paliperidone palmitate an inflammatory reaction was seen at the intramuscular injection site. Occasionally abscess formation occurred.
In rat reproduction studies with oral risperidone, which is extensively converted to paliperidone in rats and humans, adverse effects were seen on the birth weight and survival of the offspring. No embryotoxicity or malformations were observed following intramuscular administration of paliperidone palmitate to pregnant rats up to the highest dose (160 mg/kg/day) corresponding to 4.1 times the exposure level in humans at the maximum recommended dose of 150 mg. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring.
Paliperidone palmitate and paliperidone were not genotoxic. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was a statistically significant increase in mammary gland adenocarcinomas in female rats at 10, 30 and 60 mg/kg/month. Male rats showed a statistically significant increase in mammary gland adenomas and carcinomas at 30 and 60 mg/kg/month which is 1.2 and 2.2 times the exposure level at the maximum recommended human 150 mg dose. These tumours can be related to prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumour findings in rodents in terms of human risk is unknown.
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