RESUMO
JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species.
RESUMO
JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50-6000 mg) and multiple (250-2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1-3 h, except at high doses at which Cmax was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.
Assuntos
Antipiréticos , Acetaminofen/efeitos adversos , Analgésicos , Antipiréticos/efeitos adversos , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , MasculinoRESUMO
OBJECTIVE: The pharmacokinetics (PK) and safety of single oral 750-mg doses of a plant-derived pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex in the USA and Epidyolex in Europe; 100-mg/mL oral solution) were assessed in healthy adults following a high-fat/calorie meal (n = 15), a low-fat/calorie meal (n = 14), whole milk (n = 15), or alcohol (n = 14), relative to the fasted state (n = 29). METHODS: Blood samples were collected until 96 hours postdose in each period and evaluated by liquid chromatography and tandem mass spectrometry. PK parameters (maximum observed plasma concentration [Cmax ], area under the plasma concentration-time curve from time zero to the last observed quantifiable concentration, area under the concentration-time curve from time zero to infinity [AUC0-∞ ], and time to maximum plasma concentration [tmax ]) of CBD and its major metabolites were derived using noncompartmental analysis. RESULTS: CBD exposure increased by 3.8-fold for AUC0-∞ and 5.2-fold for Cmax when CBD was administered with a high-fat/calorie meal versus fasted. To a lesser extent, a low-fat/calorie meal enhanced CBD exposure versus fasted with a 2.7-fold increase in AUC0-∞ and a 3.8-fold increase in Cmax . Similarly, when dosed with whole milk, CBD exposure increased versus fasted by 2.4-fold for AUC0-∞ and 3.1-fold for Cmax . Modest elevations in CBD exposure occurred when it was dosed with alcohol: 1.6-fold for AUC0-∞ and 1.9-fold for Cmax . No clinically relevant effect of any test condition on CBD tmax or t½ versus the fasted state was apparent. The same trend was seen for the CBD metabolites, except that 7-carboxy-cannabidiol tmax was considerably longer when CBD was administered with alcohol (14 vs 4 hours fasted). Inter- and intrasubject variability in PK parameters was moderate to high during the trial. SIGNIFICANCE: CBD and metabolite exposures were most affected by a high-fat/calorie meal. CBD exposures also increased with a low-fat/calorie meal, whole milk, or alcohol, but to a lesser extent. CBD was tolerated, and there were no severe or serious adverse events during the trial.
Assuntos
Bebidas Alcoólicas , Anticonvulsivantes/farmacocinética , Canabidiol/farmacocinética , Refeições , Leite , Adulto , Idoso , Animais , Anticonvulsivantes/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Canabidiol/efeitos adversos , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Gorduras na Dieta , Ingestão de Energia , Feminino , Interações Alimento-Droga , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
BACKGROUND: Doctor shopping, defined by filling overlapping prescriptions from more than one prescriber at more than two pharmacies, is a way to obtain scheduled medications for diversion or abuse. Little is known about how far attention deficit hyperactivity disorder (ADHD) medication shoppers travel, how often they cross state lines to fill their ADHD prescriptions and how often they pay for their medication in cash, i.e. entirely out of pocket. OBJECTIVE: We sought to describe the pattern of doctor shopping for ADHD medications: how far shoppers travel, how often they cross state lines to fill their prescriptions, and how often they pay in cash. METHODS: Retrospective cohort study using LRx, a large US retail prescription database. We included subjects with any ADHD medication dispensed between 2011 and 2012. Subjects were followed for 18 months. RESULTS: Of a total of 4 402 464 subjects exposed to ADHD medications, 0.4% developed shopping behavior. Women were more likely to become shoppers. Shoppers travelled a median of 91.9 miles and non-shoppers 0.2 miles to fill their ADHD prescriptions. Almost 28% of the shoppers filled prescriptions in >1 state compared with 4.3% of non-shoppers. Of the shoppers, 27.3% paid at least one prescription in cash compared to 14.4% of the non-shoppers. CONCLUSIONS: Shoppers travelled larger distances, visited more states and paid in cash for ADHD medications more often than non-shoppers. Data sharing among prescriptions monitoring programs can improve their effectiveness and drug utilization studies should take account of cash purchases.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Comércio , Medicamentos sob Prescrição/economia , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmácias , Médicos , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Spasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. METHODS: This was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. RESULTS: Of 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were -0.23 for nabiximols and -0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. CONCLUSION: Despite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. CLINICAL TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): : NCT04657666.
Assuntos
Canabidiol , Dronabinol , Combinação de Medicamentos , Esclerose Múltipla , Espasticidade Muscular , Humanos , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Canabidiol/administração & dosagem , Canabidiol/farmacologia , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Método Duplo-Cego , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Adulto , Masculino , Sprays Orais , Feminino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
When highly purified cannabidiol (CBD; Epidiolex) and the mammalian target of rapamycin inhibitor everolimus are used concomitantly in the treatment of tuberous sclerosis complex, there is evidence of a pharmacokinetic (PK) interaction, leading to increased everolimus systemic exposure. We evaluated the effect of steady-state CBD exposure following multiple clinically relevant CBD doses on everolimus PK in healthy adult participants in a single-center, fixed-sequence, open-label, phase 1 study. All participants received oral everolimus 5 mg on day 1, followed by a 7-day washout. On days 9-17, participants received CBD (100 mg/mL oral solution) at 12.5 mg/kg in the morning and evening. On the morning of day 13, participants also received a single dose of oral everolimus 5 mg. Medications were taken 30 or 45 minutes (morning or evening dose) after starting a standardized meal. Maximum concentration and area under the concentration-time curve (AUC) from time of dosing to the last measurable concentration and extrapolated to infinity, of everolimus in whole blood were estimated using noncompartmental analysis, with geometric mean ratios and 90% confidence intervals for the ratios of everolimus dosed with CBD to everolimus dosed alone. A single dose of everolimus 5 mg was well tolerated when administered with multiple doses of CBD. Log-transformed everolimus maximum concentration, AUC from time of dosing to the last measurable concentration, and AUC extrapolated to infinity values increased by ≈2.5-fold, and everolimus half-life remained largely unchanged in the presence of steady-state CBD relative to everolimus dosed alone. Everolimus blood concentration monitoring should be strongly advised with appropriate dose reduction when coadministered with CBD.
Assuntos
Canabidiol , Adulto , Humanos , Canabidiol/efeitos adversos , Everolimo/efeitos adversos , Voluntários Saudáveis , Sirolimo/efeitos adversos , Interações MedicamentosasRESUMO
PURPOSE: Spasticity is common in multiple sclerosis (MS), often leading to functional limitations and disability. We developed a conceptual model of spasticity in MS integrating expert opinion, recent literature, and experiences of clinicians and people with MS spasticity. METHODS: A conceptual model was developed based on a targeted literature review of articles published between 2014 and 2019, followed by input from clinicians, then input from participants with MS spasticity. Multidisciplinary experts on spasticity provided guidance at each step. RESULTS: Key concepts of the integrated spasticity conceptual model included: moderators; triggers; modifiers; treatment; objective manifestations; subjective experience; physical, functional, social, and emotional/psychological impacts; and long-term consequences. Participants with MS spasticity most frequently endorsed spasms, tightness, and pain as descriptors of spasticity. Some participants with MS spasticity had difficulty distinguishing spasticity from other MS symptoms (e.g. muscle weakness). Some triggers, emotional/psychological impacts, and long-term consequences of spasticity reported by participants with MS spasticity were not previously identified in the published literature. CONCLUSIONS: This conceptual model of spasticity, integrating published literature with the experience of clinicians, people with MS spasticity, and experts, demonstrates the complex, multidimensional nature of MS spasticity. This model may be used to improve clinician-patient dialogue, research, and patient care.
Many people with multiple sclerosis (MS) have spasticity, generally in the lower limbs, but this symptom is complex and multidimensional and therefore difficult to characterize.MS spasticity may be influenced by moderators, triggers, modifiers, and treatment, all of which can affect objective measures and the subjective experience of spasticity.MS spasticity can have physical, functional, social, and emotional/psychological impacts as well as long-term consequences that can affect rehabilitation and ultimately reduce health-related quality of life for people with MS.Given that people with MS may view spasticity differently than their rehabilitation providers, providers should ask patients about their spasticity, including their moderators, triggers, modifiers, experience, impacts, long-term consequences, and effects on quality of life.This conceptual model provides a framework to improve clinician-patient dialogue, research, and rehabilitation for MS spasticity.
RESUMO
BACKGROUND: To provide a comprehensive assessment of the treatment effects of nabiximols oromucosal spray on multiple sclerosis spasticity in two clinical trials, GWSP0604 and SAVANT. METHODS: Both studies enriched for responders before randomization, defined by a ≥20% improvement in Spasticity 0-10 numeric rating scale (NRS) score. Additionally, SAVANT used randomized re-titration following washout. Spasticity NRS outcomes, spasm count, and modified Ashworth scale (MAS) scores were analyzed. RESULTS: Mean change from baseline in average daily Spasticity NRS scores was significantly larger for nabiximols than placebo at all postbaseline timepoints, ranging from -0.36 to -0.89 in GWSP0604 and -0.52 to -1.96 in SAVANT. Percent reduction in geometric mean change from baseline in average daily spasm count for nabiximols ranged from 19-35% versus placebo. A treatment difference favoring nabiximols was observed in overall MAS scores during the randomized part of each study. Treatment effect was larger for combinations of lower limb muscle groups (ranging between -0.16 and -0.37). CONCLUSIONS: Nabiximols leads to improvement in spasticity that was sustained over the 12-week treatment period as measured by average daily Spasticity NRS scores, daily spasm counts, and MAS scores for combinations of muscle groups, especially the combination of the 6 key muscle groups in the lower limbs in NRS responders to nabiximols treatment.
Assuntos
Canabidiol , Esclerose Múltipla , Humanos , Canabidiol/uso terapêutico , Dronabinol/uso terapêutico , Combinação de Medicamentos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Tono Muscular , Ensaios Clínicos Controlados Aleatórios como Assunto , Espasmo/tratamento farmacológicoRESUMO
Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS-MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners' Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression - Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Administração Oral , Adolescente , Adulto , Estimulantes do Sistema Nervoso Central/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Síndrome de Abstinência a Substâncias , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Placebo and pharmacodynamic (PD) models were developed which link temporal measures of efficacy in children with attention deficit hyperactivity disorder (ADHD) and methylphenidate (MPH) plasma concentrations from adults. These models can be used to predict daily pediatric clinical measure profiles following administration of different MPH formulations in children without conducting pediatric pharmacokinetic (PK) or PD studies by using more easily obtained adult PK data. Mean PK data from various extended-release MPH formulations studied in adults and mean PD data from nine pediatric efficacy studies were obtained from the literature. The individual time-course of the clinical measures from three pediatric trials were also analyzed after being combined with the meta-analysis data. The clinical measure profiles following placebo administration were described by indirect response models with time-varying elimination rates. MPH pharmacodynamic effect was described by E(max) models, which included time-dependent tolerance. Internal and external evaluations using a visual predictive check technique confirmed the prediction capability of the models. This modeling exercise demonstrated that time courses of MPH concentrations in adults with different drug release patterns can be used to predict time courses of clinical efficacy parameters in pediatrics by employing the models developed by meta-analysis.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Metilfenidato/farmacocinética , Modelos Biológicos , Criança , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
OBJECTIVE: To evaluate the long-term safety of OROS methylphenidate in the management of attention-deficit/hyperactivity disorder (ADHD) in adults. METHODS: This multicenter, open-label, dose-titration, flexible dose study enrolled adults with ADHD for 6 or 12 months of treatment with OROS methylphenidate. Dosing began at 36 mg/d, with titration in 18-mg increments every 7 days until a predefined outcome (efficacy threshold, maximum dosage of 108 mg/d, or limiting adverse event). Dose reduction occurred for prespecified reasons, and the subjects discontinued if unable to tolerate 36 mg/d. Assessments included ADHD symptoms, adverse events, vital signs, and laboratory results. RESULTS: A total of 550 subjects received treatment (52% were men; mean age, 39 years; range, 18-65 years), and 57% (146/258) and 44% (129/292) completed their 6 or 12 months of treatment with mean durations of 128 and 213 days, respectively. The final prescribed dosages were 36 mg/d (22.4%), 54 mg/d (25.1%), 72 mg/d (22.0%), 90 mg/d (17.1%), and 108 mg/d (13.5%). Modest increases from baseline to final visit were observed in mean systolic (2.6 mm Hg) and diastolic (1.9 mm Hg) blood pressure and pulse (4.1 beats per minute). The mean weight decreased by 2.3 kg. No clinically meaningful changes in laboratory values or electrocardiogram parameters were observed other than increased heart rate. Most common adverse events included decreased appetite (26.7%), headache (24.0%), and insomnia (20.7%). No serious adverse event was considered related to study medication. Several measures of efficacy indicated improvement during the study. CONCLUSIONS: OROS methylphenidate, in the flexible dosage range from 36 to 108 mg/d, was well tolerated for up to 1 year in adults with ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Metilfenidato/efeitos adversos , Metilfenidato/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Masculino , Metilfenidato/administração & dosagem , Pessoa de Meia-Idade , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVES: To evaluate the antimanic efficacy and safety of paliperidone extended-release (ER) tablets in patients with bipolar I disorder. METHODS: This study included a 3-week, double-blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9-week, double-blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score >or= 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3-12 mg/day), quetiapine (400-800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. RESULTS: Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome; least-squares mean difference in change from baseline in YMRS scores [95% confidence interval (CI)]: -5.5 (-7.57; -3.35); p < 0.001} and noninferior to quetiapine at the 12-week endpoint [least-squares mean difference (95% CI): 1.7 (-0.47; 3.96)]. The median mode dose during the 12-week treatment period was 9 mg for paliperidone ER and 600 mg for quetiapine. The most common (>or= 10%) treatment-emergent adverse events during the 12-week period were: headache (16%), somnolence (10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight increase >or= 7% from baseline to 12-week endpoint was 8% with paliperidone ER and 17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus quetiapine patients (7.5%) 'switched to depression' at the12-week endpoint. CONCLUSIONS: Paliperidone ER (3-12 mg/day) was efficacious and tolerable in the treatment of acute mania.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Isoxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Transtorno Bipolar/classificação , Dibenzotiazepinas/uso terapêutico , Método Duplo-Cego , Sistemas de Liberação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona , Escalas de Graduação Psiquiátrica , Fumarato de Quetiapina , Resultado do TratamentoRESUMO
Long-term efficacy and safety of paliperidone extended-release tablets (3-12 mg/day) were evaluated in pooled data from 52-week open-label extension (OLE) phases of three 6-week, placebo-controlled, double-blind (DB) trials involving 1083 schizophrenia patients. Forty-seven percent of patients completed the OLE phase. Outcome measures included Positive and Negative Syndrome Scale and Personal and Social Performance scale scores. Improvements observed on both scales in active treatment groups during the DB phases were maintained during the OLE phase. Most commonly (> or =10% patients) reported adverse events (AEs) were insomnia, headache, and akathisia. One or more serious AEs were reported by 16% of patients; two patients had a treatment-emergent AE that resulted in death (suicide). Extrapyramidal symptom-related AEs were reported by 25% of patients. Median maximum movement disorder rating scale scores indicated no severity change during the OLE. Mean (+/-SD) increase in body weight from OLE baseline to end point was 1.1+/-5.47 kg across treatment groups and there were no clinically meaningful changes for plasma glucose, insulin or lipid levels. This analysis shows that paliperidone extended-release can maintain improvements in symptoms and functioning and is generally well tolerated for up to 52 weeks in schizophrenia patients.
Assuntos
Antipsicóticos/administração & dosagem , Isoxazóis/administração & dosagem , Pirimidinas/administração & dosagem , Esquizofrenia/tratamento farmacológico , Doença Aguda , Administração Oral , Adulto , Antipsicóticos/efeitos adversos , Ensaios Clínicos como Assunto , Preparações de Ação Retardada , Feminino , Humanos , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Palmitato de Paliperidona , Escalas de Graduação Psiquiátrica , Pirimidinas/efeitos adversos , Psicologia do Esquizofrênico , Índice de Gravidade de Doença , Comprimidos , Fatores de Tempo , Resultado do TratamentoAssuntos
Antipsicóticos/efeitos adversos , Isoxazóis/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Pirimidinas/efeitos adversos , Animais , Antipsicóticos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Isoxazóis/administração & dosagem , Palmitato de Paliperidona , Pirimidinas/administração & dosagem , Fatores de RiscoRESUMO
OBJECTIVE: To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation. METHODS: Data were drawn from 3 similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for ≥ 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models. RESULTS: Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval [CI]) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M. CONCLUSIONS: Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515.
Assuntos
Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Síndrome de Abstinência a Substâncias/sangue , Administração Oral , Adulto , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Injeções Intramusculares , Masculino , Palmitato de Paliperidona/efeitos adversos , Recidiva , Medição de Risco , Relação Estrutura-AtividadeRESUMO
The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified.
Assuntos
Antimaníacos/sangue , Antipsicóticos/sangue , Transtornos Mentais/sangue , Transtornos Mentais/tratamento farmacológico , Palmitato de Paliperidona/sangue , Ácido Valproico/sangue , Adulto , Antimaníacos/administração & dosagem , Antipsicóticos/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/administração & dosagem , Comprimidos , Ácido Valproico/administração & dosagemRESUMO
Paliperidone palmitate (PP) is a once-monthly long-acting injectable antipsychotic approved for the treatment of schizophrenia in many countries. To evaluate the different injection-site options, we compared the pharmacokinetic profile of paliperidone after multiple injections of PP 100 mg eq. (156 mg of PP, equivalent to 100 mg of paliperidone) on days 1, 8, 36, and 64 into the deltoid (n = 24) or gluteal muscle (n = 25) in patients with schizophrenia. After four injections in the deltoid muscle, paliperidone exposure was higher for AUCτ and Cmax , compared with the gluteal muscle (geometric mean AUCτ -based ratio: 120% [90% CI: 93.1-154.7%], and geometric mean Cmax -based ratio: 130% [90% CI: 100.6-168.9%]). The mean [SD] fluctuation index was higher, with a larger interpatient variability, after deltoid-injections (75.9% [30.9%]) than gluteal-injections (58.5% [14.3%]). The median tmax was similar for both sites. PP was generally tolerable in patients, with more favorable local-site tolerability for gluteal-injection. In conclusion, to achieve therapeutic-concentrations quickly, the first-two injections of PP are best administered into the deltoid muscle, whereas thereafter maintenance-injections can be administered either in the deltoid or gluteal muscle.
Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Área Sob a Curva , Nádegas , Croácia , Músculo Deltoide , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Injeções Intramusculares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Palmitato de Paliperidona/efeitos adversos , Palmitato de Paliperidona/sangue , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Resultado do Tratamento , Adulto JovemRESUMO
IMPORTANCE: Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients. OBJECTIVE: To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms. DESIGN, SETTING, AND PARTICIPANTS: This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase. INTERVENTIONS: Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase. MAIN OUTCOMES AND MEASURES: Time from randomization to the first relapse event (time to relapse) in the DB phase. RESULTS: In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%). CONCLUSIONS AND RELEVANCE: Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01529515.
Assuntos
Isoxazóis/uso terapêutico , Palmitatos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Prevenção Secundária/métodos , Adolescente , Adulto , Idoso , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona , Palmitatos/administração & dosagem , Palmitatos/efeitos adversos , Esquizofrenia/prevenção & controle , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: This commentary summarizes recommended dosing strategies for a recently developed 3 monthly long-acting injectable 1 (LAI) formulation of paliperidone palmitate (PP3M) for the treatment of schizophrenia in adults. METHODS: Recommendations for different dosing scenarios are based on the pharmacokinetic, efficacy and safety outcomes from phase 1 and phase 3 studies, population pharmacokinetic models, and model based simulations. RESULTS: Switching to PP3M treatment is recommended only in patients previously treated with once monthly paliperidone palmitate LAI (PP1M) for at least 4 months. The first injection of PP3M (175 to 525 mg equivalent [eq.]) should be given at the time of next scheduled injection of PP1M as a 3.5-fold multiple of the last PP1M dose (50-150 mg eq.), with a dosing window of ± 1 week. Following that first injection of PP3M, once-every-three-months maintenance injections with PP3M are recommended, with a dosing window of ± 2 weeks. The doses of PP3M can be administered in either deltoid (≥ 90 kg: 1.5 inch 22 G needle; <90 kg: 1.0 inch 22 G needle) or gluteal muscles (1.5 inch 22 G needle regardless of weight). In patients with mild renal impairment (creatinine clearance: 50-80 mL/min), a 25% dose reduction in PP1M and subsequent switching to a corresponding 3.5-dose multiple of PP3M (but not exceeding 350 mg eq.) is recommended. Appropriate dosing is recommended in elderly patients with diminished renal function not exceeding mild renal impairment. Similarly to PP1M, PP3M is not recommended in patients with moderate/severe renal impairment. Like PP1M, no dosage adjustment is required in patients with mild or moderate hepatic impairment or elderly patients with normal renal function. CONCLUSIONS: These data provide clinical guidelines for the optimum use of PP3M in patients with schizophrenia previously treated with PP1M for at least 4 months. REGISTRATION: ClinicalTrials.gov identifier: NCT01559272 and NCT01529515.
Assuntos
Antipsicóticos/administração & dosagem , Palmitato de Paliperidona/administração & dosagem , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Química Farmacêutica , Humanos , Injeções Intramusculares , Músculo EsqueléticoRESUMO
Given the potential concomitant use of carbamazepine and paliperidone extended-release (ER) in the treatment of schizophrenia or schizoaffective disorder, this open-label, two-treatment sequential study investigated the effect of repeated administration of carbamazepine on the steady-state pharmacokinetics of paliperidone. Sixty-four patients with a diagnosis of schizophrenia or bipolar-I disorder received the following treatments in a fixed sequential order, without washout between treatments: (i) paliperidone ER 6 mg tablet once daily for 7 days, and (ii) paliperidone ER 6 mg once daily concomitantly with carbamazepine 200 mg twice daily for the subsequent 21 days. Upon coadministration with carbamazepine, paliperidone steady-state total exposure (AUC24 h ) and peak plasma concentrations (Cmax ) decreased by approximately 37% [LSM ratio-AUC24 h : 63.4 (90% CI: 57.19; 70.29); Cmax : 62.47 (90% CI: 55.77; 69.98)]. This decrease is accounted for to a substantial degree by a 35% increase in renal clearance of paliperidone, likely as a result of induction of renal P-glycoprotein by carbamazepine. A 14% decrease in the amount of drug excreted unchanged in the urine suggests that carbamazepine coadministration has a limited effect on the intestinal absorption or cytochrome metabolism of paliperidone.