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AIM: We assessed the dosage strengths of paliperidone palmitate 1-month (PP1M) long-acting injectable resulting in similar steady-state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. METHODS: Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. RESULTS: Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25-fold dose conversion factor from oral risperidone to PP1M). CONCLUSIONS: This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another.
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Antipsicóticos , Palmitato de Paliperidona , Risperidona , Esquizofrenia/tratamiento farmacológico , Administración Oral , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Preparaciones de Acción Retardada/administración & dosificación , Humanos , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/uso terapéutico , Guías de Práctica Clínica como Asunto , Risperidona/farmacocinética , Risperidona/uso terapéutico , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18-70 years) with schizophrenia, previously stabilized on PP1M. METHODS: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. RESULTS: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. CONCLUSION: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.
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Palmitato de Paliperidona/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antipsicóticos/efectos adversos , Antipsicóticos/sangre , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Palmitato de Paliperidona/efectos adversos , Palmitato de Paliperidona/sangre , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/sangre , Prevención Secundaria , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: To prospectively select the dose of the paliperidone palmitate 3-month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1-month (PP1M) formulation previously approved for schizophrenia treatment. METHODS: Pharmacokinetic (PK) data from a 6-month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population-PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M-to-PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple-dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped. RESULTS: Prospective steady-state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study. CONCLUSIONS: Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3-5 years and may be applicable to other drug development projects.
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Esquema de Medicación , Composición de Medicamentos , Palmitato de Paliperidona/administración & dosificación , Palmitato de Paliperidona/farmacocinética , Adolescente , Adulto , Anciano , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Cálculo de Dosificación de Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Palmitato de Paliperidona/sangre , Estudios Prospectivos , Esquizofrenia/sangre , Adulto JovenRESUMEN
Domperidone is a dopamine receptor antagonist and a substrate of CYP3A4, hence there is a potential for CYP3A inhibition-based drug-drug interactions (DDI). A physiologically based pharmacokinetic model was developed to describe DDIs between domperidone and three different inhibitors of CYP3A4. Simcyp V13.1 was used to simulate human domperidone pharmacokinetics and DDIs. Inputs included domperidone chemical and physical properties (LogP, pKa, etc.), in vitro human liver microsomal data and pharmacokinetic parameters from single-dose intravenous clinical studies in healthy participants. The simulated mean maximum domperidone plasma concentration and AUC after single- and multiple-oral doses under diverse conditions were within 1.1-1.4 fold of the observed values. The simulated intestinal availability, hepatic availability and the fraction absorbed were 0.45 ± 0.14, 0.31 ± 0.10 and 0.89 ± 0.11, respectively, and comparable to observed in vivo values. The simulated ratios of AUC and C(max) in the presence of ketoconazole, erythromycin or itraconazole to baseline were consistent with the observed ratios. Simulated ketoconazole, erythromycin, itraconazole and C(max,ss) and AUC(ss) were within 1.5-fold of the observed values.
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Inhibidores del Citocromo P-450 CYP3A/farmacología , Domperidona/farmacocinética , Antagonistas de Dopamina/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Células CACO-2 , Simulación por Computador , Interacciones Farmacológicas , Eritromicina/farmacología , Femenino , Humanos , Itraconazol/farmacología , Cetoconazol/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Adulto JovenRESUMEN
Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.
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Farmacología Clínica , Humanos , Investigación Biomédica Traslacional , Ciencia Traslacional BiomédicaRESUMEN
Despite the liver being the primary site for clearance of xenobiotics utilizing a myriad of mechanisms ranging from cytochrome P450 enzyme pathways, glucuronidation, and biliary excretion, there is a dearth of information available as to how the severity of hepatic impairment (HI) can alter drug absorption and disposition (i.e., pharmacokinetics [PK]) as well as their efficacy and safety or pharmacodynamics (PD). In general, regulatory agencies recommend conducting PK studies in subjects with HI when hepatic metabolism/excretion accounts for more than 20% of drug elimination or if the drug has a narrow therapeutic range. In this tutorial, we provide an overview of the global regulatory landscape, clinical measures for hepatic function assessment, methods to stage HI severity, and consequently the impact on labeling. In addition, we provide an in-depth practical guidance for designing and conducting clinical trials for patients with HI and on the application of modeling and simulation strategies in lieu of dedicated trials for dosing recommendations in patients with HI.
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Sistema Enzimático del Citocromo P-450 , Eliminación Hepatobiliar , Hepatopatías , Humanos , Sistema Enzimático del Citocromo P-450/metabolismo , Eliminación Hepatobiliar/fisiología , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismoRESUMEN
An impaired renal function, including acute and chronic kidney disease and end-stage renal disease, can be the result of aging, certain disease conditions, the use of some medications, or as a result of smoking. In patients with renal impairment (RI), the pharmacokinetics (PKs) of drugs or drug metabolites may change and result in increased safety risks or decreased efficacy. In order to make specific dose recommendations in the label of drugs for patients with RI, a clinical trial may have to be conducted or, when not feasible, modeling and simulations approaches, such as population PK modeling or physiologically-based PK modelling may be applied. This tutorial aims to provide an overview of the global regulatory landscape and a practical guidance for successfully designing and conducting clinical RI trials or, alternatively, on applying modeling and simulation tools to come to a dose recommendation for patients with RI in the most efficient manner.
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Lesión Renal Aguda/complicaciones , Relación Dosis-Respuesta a Droga , Fallo Renal Crónico/complicaciones , Riñón/fisiopatología , Modelos Biológicos , Lesión Renal Aguda/fisiopatología , Ensayos Clínicos como Asunto , Simulación por Computador , Tasa de Filtración Glomerular/fisiología , Humanos , Fallo Renal Crónico/fisiopatología , Eliminación Renal/fisiologíaRESUMEN
This review aimed to evaluate the clinical success of clopidogrel dosing based on CYP2C19 genotype and to identify the relevant additional factors that may be useful for consideration by the clinician when dosing individuals with clopidogrel. The results indicated that genotype-guided dosing in individuals with acute coronary syndrome undergoing percutaneous coronary intervention is frequently practiced, although the advantages remain controversial. Demographic factors, such as age, ethnicity, and some comorbidities, such as diabetes mellitus, can potentially contribute to further refinement of clopidogrel dosage but additional clinical studies to guide these practices are required. Drugs that are CYP2C19 or CYP3A4 inhibitors may reduce the effectiveness of clopidogrel and should be carefully considered during co-administration. In particular, as stated in the clopidogrel label, concomitant use with strong or moderate CYP2C19 inhibitors, such as omeprazole, should be avoided. Increased exposure and response to clopidogrel has been observed in smokers. Noteworthy, a very recent study has shown that smoking cessation in clopidogrel patients may result in reduced response and carries the risk of high on-clopidogrel platelet reactivity. Recent studies have shown clinically significant increases in exposure to CYP2C8 substrates (repaglinide, dasabuvir, and desloratadine) and a CYP2B6 substrate (s-sibutramine) following co-administration with clopidogrel, indicating that therapeutic strategies with clopidogrel should avoid these drugs.
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Clopidogrel/administración & dosificación , Citocromo P-450 CYP2C19/genética , Inhibidores del Citocromo P-450 CYP2C19/farmacología , Interacciones Farmacológicas , Etnicidad , Genotipo , Humanos , Variantes Farmacogenómicas , Inhibidores de Agregación Plaquetaria/administración & dosificación , Polimorfismo Genético , Medicina de Precisión , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , FumarRESUMEN
[18F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (VT) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose VT,IDIF values were compared with corresponding VT,AIF estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose VT,IDIF values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for VT,IDIF compared to 0.97 ± 0.01 for VT,AIF. These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [18F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility.
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Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Adulto , Radioisótopos de Flúor/sangre , Radioisótopos de Flúor/farmacocinética , Humanos , Imagenología Tridimensional , Ligandos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiofármacos/sangre , Radiofármacos/farmacocinética , Receptores Purinérgicos P2X7/sangre , Adulto JovenRESUMEN
Positron emission tomography (PET) provides useful information in target engagement or receptor occupancy in the brain for central nervous system (CNS) drug development, however, dose selection for human PET studies is challenging and largely empirical. Here, we describe a translational pharmacokinetic/pharmacodynamic (PK/PD) modeling work to inform dose selection for a human PET study of JNJ-54175446, a CNS-penetrating P2X7 receptor antagonist. Models were developed using data on monkey brain occupancy and plasma drug exposures from a monkey PET study and early human clinical studies that provided data on drug exposures and human ex vivo-stimulated peripheral interleukin (IL)-1ß release. The observed plasma PK of JNJ-54175446 in human was adequately described by a one-compartment model with parallel zero-order and first-order absorption and first-order elimination. An exposure-occupancy model was extrapolated from monkey to human assuming a similar unbound potency (all other model parameters remained unchanged). This model was then used to simulate human brain occupancy to guide human PET study dose selection, together with the human population PK model. The corroboration of model predicted occupancy by the observed occupancy data from the human PET study supports the use of a monkey as a predictive model for human PET target engagement. Potency estimate for brain occupancy was generally comparable to that for the suppression of the provoked peripheral IL-1ß release ex vivo, indicating that blood IL-1ß release may be used as a surrogate of central occupancy for JNJ-54175446. Translational PK/PD modeling approach could be used for selecting optimal doses for human PET and other clinical studies.
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Tomografía de Emisión de Positrones , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/farmacocinética , Radiofármacos/farmacocinética , Receptores Purinérgicos P2X7/metabolismo , Triazoles/farmacocinética , Adolescente , Adulto , Anciano , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Ensayos Clínicos Fase I como Asunto , Simulación por Computador , Conjuntos de Datos como Asunto , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos/métodos , Femenino , Radioisótopos de Flúor/administración & dosificación , Humanos , Interleucina-1beta/metabolismo , Macaca mulatta , Masculino , Persona de Mediana Edad , Modelos Biológicos , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Piridinas/administración & dosificación , Cintigrafía , Radiofármacos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Triazoles/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography. AIMS: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. METHODS: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. RESULTS: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. CONCLUSION: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.
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Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Triazoles/farmacología , Adolescente , Adulto , Estimulantes del Sistema Nervioso Central/administración & dosificación , Trastorno Depresivo Mayor/tratamiento farmacológico , Dextroanfetamina/administración & dosificación , Método Doble Ciego , Electroencefalografía , Humanos , Inflamación/tratamiento farmacológico , Masculino , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Antagonistas del Receptor Purinérgico P2X/efectos adversos , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Investigación Biomédica Traslacional , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/farmacocinética , Adulto JovenRESUMEN
PURPOSE: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to assess the efficacy and safety of paliperidone palmitate 3-month (PP3M) vs 1-month formulation (PP1M) in European and non-European patients with schizophrenia. PATIENTS AND METHODS: In this randomized, DB, parallel-group study, adult patients (18-70 years) with schizophrenia (per DSM-IV-TR) having Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120; previously stabilized on PP1M were enrolled. The study had 4 phases: screening (3 weeks), open-label (OL) stabilization (17 weeks), DB (48 weeks) and follow-up (4-12 weeks) phase. Patients were treated with fixed-dose PP3M (175-525 mg eq deltoid/gluteal) or PP1M (50-150 mg eq deltoid/gluteal) for 48 weeks in DB phase. RESULTS: In total, 487 European (PP3M, n=242; PP1M, n=245) and 508 non-European patients (PP3M, n=241; PP1M, n=267) entered DB phase (modified intent-to-treat (mITT) [DB] analysis set). Among the 508 non-European patients in mITT set, 67.7% were from Asia (n=344) and 32.3% were from rest of world (ROW, n=164). During the DB phase, similar percentage of Europeans (PP3M: 7%; PP1M: 8%) and non-Europeans (PP3M: 9%; PP1M: 10%) experienced relapse (Kaplan-Meier estimate PP3M-PP1M [95% CI] of percentage of relapse-free patients at the end of DB phase [primary endpoint]: European: 1.0% [-4.3%; 6.2%]; non-European: 1.4% [-4.4%; 7.1%]; Asian: 1.6% [-5.7%; 9.0%]; and ROW: 1.4% [-7.0%, 9.8%], per-protocol analysis set). Incidence of treatment-emergent adverse events (TEAEs) was lower in Europeans (PP3M: 56%, PP1M: 59%) than non-Europeans (PP3M: 80%, PP1M: 73%). The most commonly reported TEAE was weight gain. CONCLUSION: PP3M showed similar efficacy to PP1M in Europeans and non-Europeans, consistent with non-inferiority of PP3M to PP1M observed in overall population. Rates of AEs were higher in non-Europeans. However, weight gain was greater in non-Europeans, especially the Asian population.
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The P2X7 receptor (P2X7R) is an adenosine triphosphate-gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7-specific PET ligand 18F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1- and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (VT). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26-97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18F-JNJ-64413739 PET/MRI scans 4-6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5-300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose VTResults: The average (mean ± SD) effective dose was 22.0 ± 1.0 µSv/MBq. The 2-tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model VT values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject VT variability was relatively high, with cortical VT showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model VT and 11.9% ± 2.2% for LGA VT P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion:18F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection.
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Modelos Biológicos , Péptidos/farmacocinética , Tomografía de Emisión de Positrones , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacología , Receptores Purinérgicos P2X7/metabolismo , Triazoles/farmacología , Adulto , Voluntarios Sanos , Humanos , Cinética , Ligandos , Masculino , Radiometría , Reproducibilidad de los Resultados , Distribución Tisular/efectos de los fármacos , Adulto JovenRESUMEN
INTRODUCTION: In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat. METHODS: Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis. RESULTS: SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days. DISCUSSION: SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.
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Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Fluoresceína/farmacocinética , Colorantes Fluorescentes/farmacocinética , Neurotoxinas , Enfermedad de Parkinson Secundaria/inducido químicamente , Rotenona , Análisis de Varianza , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Conducta Animal , Transporte Biológico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Bombas de Infusión Implantables , Masculino , Microdiálisis , Actividad Motora , Neurotoxinas/administración & dosificación , Neurotoxinas/toxicidad , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/psicología , Ratas , Ratas Endogámicas Lew , Rotenona/administración & dosificación , Rotenona/toxicidadRESUMEN
BACKGROUND: Central nervous system-derived interleukin-1ß plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1ß. AIMS: This first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants. METHODS: The study had three parts: an ascending-dose study in fasted participants (0.5-300 mg JNJ-54175446); an ascending-dose study in fed participants (50-600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC)50 (105 ng/mL) and EC90 (900 ng/mL) values for central nervous system P2X7 receptor binding. RESULTS: Seventy-seven participants received a single oral dose of JNJ-54175446 ( n=59) or placebo ( n=18). Area under the curve of concentration time extrapolated to infinity (AUC∞) increased dose-proportionally; maximum concentration (Cmax) of plasma (Cmax,plasma) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest Cmax,plasma reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 Cmax in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound Cmax,plasma and Cmax,CSF were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3'-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1ß release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC)50:82 ng/mL; 95% confidence interval: 48-94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%). CONCLUSION: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1ß release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.
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Encéfalo/metabolismo , Interleucina-1beta/metabolismo , Antagonistas del Receptor Purinérgico P2X/administración & dosificación , Piridinas/administración & dosificación , Triazoles/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Interacciones Alimento-Droga , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Masculino , Persona de Mediana Edad , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Distribución Tisular , Triazoles/farmacocinética , Triazoles/farmacología , Adulto JovenRESUMEN
OBJECTIVE: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. PATIENTS AND METHODS: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50-150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan-Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. RESULTS: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P<0.001) following treatment with PP3M/PP1M. Frequency of treatment-emergent adverse events in PP3M group during DB phase was greater in the East Asian subgroup (81%) than the global population (68%) and was higher in Japan (92%) than China (75%). CONCLUSION: Results suggest that PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified.
RESUMEN
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 â¼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was â¼100% 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.