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BACKGROUND: Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug interaction (DDI) profile of padsevonil. RESEARCH DESIGN AND METHODS: An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided. RESULTS: In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed. CONCLUSIONS: The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.
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PURPOSE: Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson's disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. PROCEDURES: In the preclinical study, two radiolabeling positions were investigated on the S-enantiomer of minzasolmin (UCB2713): [11C]methylamine UCB2713 ([11C-N-CH3]UCB2713) and [11C]carbonyl UCB2713 ([11C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [11C-N-CH3]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice (n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [11C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. PRIMARY OBJECTIVE: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. RESULTS: Preclinical data supported the use of [11C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers (N = 4). The mean estimated whole brain total distribution volume (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% (n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. CONCLUSION: Following positive preclinical results with the N-methyl labeled PET tracer, [11C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood-brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones , Humanos , Masculino , Ratones , Animales , Distribución Tisular , Tomografía de Emisión de Positrones/métodos , Encéfalo , Barrera HematoencefálicaRESUMEN
Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).
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Pruebas con Sangre Seca , Espectrometría de Masas en Tándem , Humanos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Recolección de Muestras de Sangre , Atención Dirigida al PacienteRESUMEN
Objective: Translocator protein (TSPO) targeting positron emission tomography (PET) imaging radioligands have potential utility in epilepsy to assess the efficacy of novel therapeutics for targeting neuroinflammation. However, previous studies in healthy volunteers have indicated limited test-retest reliability of TSPO ligands. Here, we examine test-retest measures using TSPO PET imaging in subjects with epilepsy and healthy controls, to explore whether this biomarker can be used as an endpoint in clinical trials for epilepsy. Methods: Five subjects with epilepsy and confirmed mesial temporal lobe sclerosis (mean age 36 years, 3 men) were scanned twice-on average 8 weeks apart-using a second generation TSPO targeting radioligand, [11C]PBR28. We evaluated the test-retest reliability of the volume of distribution and derived hemispheric asymmetry index of [11C]PBR28 binding in these subjects and compared the results with 8 (mean age 45, 6 men) previously studied healthy volunteers. Results: The mean (± SD) of the volume of distribution (VT), of all subjects, in patients living with epilepsy for both test and retest scans on all regions of interest (ROI) is 4.49 ± 1.54 vs. 5.89 ± 1.23 in healthy volunteers. The bias between test and retest in an asymmetry index as a percentage was small (-1.5%), and reliability is demonstrated here with Bland-Altman Plots (test mean 1.062, retest mean 2.56). In subjects with epilepsy, VT of [11C]PBR28 is higher in the (ipsilateral) hippocampal region where sclerosis is present than in the contralateral region. Conclusion: When using TSPO PET in patients with epilepsy with hippocampal sclerosis (HS), an inter-hemispheric asymmetry index in the hippocampus is a measure with good test-retest reliability. We provide estimates of test-retest variability that may be useful for estimating power where group change in VT represents the clinical outcome.
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Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.
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11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution (VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by â¼35-40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.
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Sustancia Blanca/diagnóstico por imagen , Adulto , Anciano , Algoritmos , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Levetiracetam/farmacología , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Tomografía de Emisión de Positrones , Radiofármacos , Estándares de Referencia , Sustancia Blanca/efectos de los fármacosRESUMEN
OBJECTIVE: To assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). METHODS: Data were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1-2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4-8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50-200â¯mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80-1.25 limits. RESULTS: Within the population for analysis (nâ¯=â¯1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. CONCLUSION: In adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.
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Anticonvulsivantes/uso terapéutico , Carbamazepina/análogos & derivados , Pirrolidinonas/farmacología , Convulsiones/tratamiento farmacológico , Adulto , Carbamazepina/farmacocinética , Epilepsia Refractaria/tratamiento farmacológico , Epilepsias Parciales/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11 C-UCB-J (EP0074; NCT02602860). METHODS: Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50-200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice-daily oral dosing of BRV (50-100 mg) and 4 hours postdose of LEV (250-600 mg). Half-time of 11 C-UCB-J signal change was computed from displacement measurements. Half-saturation concentrations (IC50 ) were determined from calculated SO. RESULTS: Observed tracer displacement half-times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half-times were 8 minutes shorter. The SO was 66%-70% for 100 mg intravenous BRV, 84%-85% for 200 mg intravenous BRV, and 78%-84% for intravenous 1500 mg LEV. The IC50 of BRV (0.46 µg/mL) was 8.7-fold lower than of LEV (4.02 µg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%-87% (peak) and 76%-82% (trough). SIGNIFICANCE: BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.
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Anticonvulsivantes/farmacocinética , Levetiracetam/farmacocinética , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuroimagen/métodos , Tomografía de Emisión de Positrones , Pirrolidinonas/farmacocinética , Administración Oral , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/metabolismo , Radioisótopos de Carbono , Femenino , Voluntarios Sanos , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Levetiracetam/administración & dosificación , Levetiracetam/sangre , Levetiracetam/metabolismo , Imagen por Resonancia Magnética , Masculino , Unión Proteica , Pirrolidinonas/administración & dosificación , Pirrolidinonas/sangre , Pirrolidinonas/metabolismoRESUMEN
In this phase I, single-center, open-label study of ten heathy adults (18-45 years; NCT02647697), the PK, safety, and tolerability profile of radiprodil oral suspension in healthy adults were assessed, as well as two PK microsampling techniques. All participants received a single 30 mg radiprodil dose (12 mL oral suspension). Blood was collected at various time points using conventional venous sampling (intravenous catheter or venepuncture), and Mitra™ and Aqua-Cap™ Drummond microsampling (finger-prick and blood taken from venous blood sample tubes). Geometric mean radiprodil plasma concentrations from conventional venous samples were above the lower limit of quantification up to 48 hours after administration of a single oral dose of radiprodil. Geometric mean AUC inf and Cmax were 2042 h ng mL -1 and 89.4 ng mL -1, respectively. Geometric mean t½ was 15.8 hour; median tmax was 4 hour (range: 3-6 hour). Radiprodil exposure variables for Aqua-Cap™ Drummond sampling were similar to the conventional venous-derived data. Conversely, radiprodil exposure variables were lower with Mitra™ sampling compared with conventional venous sampling. The geometric mean ratio (90% confidence interval) for Cmax of conventional venous versus Mitra™ and Aqua-Cap™ Drummond sampling (finger-prick blood) was 0.89 (0.85, 0.94) and 1.03 (0.97,1.08), respectively, and therefore within the conventional bioequivalence range (0.80-1.25). Radiprodil oral suspension had an acceptable safety, tolerability, and palatability profile. The PK profile of radiprodil oral suspension was established in healthy adults, and was comparable when analyzed using conventional versus microsampling techniques. These results will support future radiprodil paediatric studies.
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Acetamidas/farmacocinética , Recolección de Muestras de Sangre/métodos , Piperidinas/farmacocinética , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Acetamidas/administración & dosificación , Acetamidas/efectos adversos , Administración Oral , Adulto , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Femenino , Voluntarios Sanos , Humanos , Masculino , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Suspensiones , Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Adulto JovenRESUMEN
INTRODUCTION: Clinical assessment of motor symptoms in Parkinson's disease (PD) is subjective and may not reflect patient real-world experience. This two-part pilot study evaluated the accuracy of the NIMBLE wearable biosensor patch (containing an accelerometer and electromyography sensor) to record body movements in clinic and home environments versus clinical measurement of motor symptoms. METHODS: Patients (Hoehn & Yahr 2-3) had motor symptom fluctuations and were on a stable levodopa dose. Part 1 investigated different sensor body locations (six patients). In Part 2, 21 patients wore four sensors (chest, and most affected side of shin, forearm and back-of-hand) during a 2-day clinic- and 1-day home-based evaluation. Patients underwent Unified Parkinson's Disease Rating Scale assessments on days 1-2, and performed pre-defined motor activities at home on day 3. An algorithm estimated motor-symptom severity (predicted scores) using patch data (in-clinic); this was compared with in-clinic motor symptom assessments (observed scores). RESULTS: The overall correlation coefficient between in-clinic observed and sensor algorithm-predicted scores was 0.471 (pâ¯=â¯0.031). Predicted and observed scores were identical 45% of the time, with a predicted score within a ±1 range 91% of the time. Exact accuracy for each activity varied, ranging from 32% (pronation/supination) to 67% (rest-tremor-amplitude). Patients rated the patch easy-to-use and as providing valuable data for managing PD symptoms. Overall patch-adhesion success was 97.2%. The patch was safe and generally well tolerated. CONCLUSIONS: This study showed a correlation between sensor algorithm-predicted and clinician-observed motor-symptom scores. Algorithm refinement using patient populations with greater symptom-severity range may potentially improve the correlation.
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Acelerometría/instrumentación , Electromiografía/instrumentación , Enfermedad de Parkinson/fisiopatología , Dispositivos Electrónicos Vestibles , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Tecnología InalámbricaRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with diffuse immune cell dysfunction. CD40-CD40 ligand (CD40L) interaction activates B cells, antigen-presenting cells and platelets. CD40L blockade might provide an innovative treatment for systemic autoimmune disorders. We investigated the safety and clinical activity of dapirolizumab pegol, a polyethylene glycol conjugated anti-CD40L Fab' fragment, in patients with SLE. METHODS: This 32-week randomised, double-blind, multicentre study (NCT01764594) evaluated repeated intravenous administration of dapirolizumab pegol in patients with SLE who were positive for/had history of antidouble stranded DNA/antinuclear antibodies and were on stable doses of immunomodulatory therapies (if applicable). Sixteen patients were randomised to 30 mg/kg dapirolizumab pegol followed by 15 mg/kg every 2 weeks for 10 weeks; eight patients received a matched placebo regimen. Randomisation was stratified by evidence of antiphospholipid antibodies. Patients were followed for 18 weeks after the final dose. RESULTS: No serious treatment-emergent adverse events, thromboembolic events or deaths occurred. Adverse events were mild or moderate, transient and resolved without intervention. One patient withdrew due to infection.Efficacy assessments were conducted only in patients with high disease activity at baseline. Five of 11 (46%) dapirolizumab pegol-treated patients achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment response (vs 1/7; 14% placebo) and 5/12 (42%) evaluable for SLE Responder Index-4 responded by week 12 (vs 1/7; 14% placebo). Mechanism-related gene expression changes were observed in blood RNA samples. CONCLUSIONS: Dapirolizumab pegol could be an effective biological treatment for SLE. Further studies are required to address efficacy and safety. TRIAL REGISTRATION NUMBER: NCT01764594.
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Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Transcriptoma/efectos de los fármacos , Administración Intravenosa , Adolescente , Adulto , Anciano , Ligando de CD40/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana Edad , ARN/sangre , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenAsunto(s)
Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/sangre , Disponibilidad Biológica , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinonas/efectos adversos , Pirrolidinonas/sangre , Soluciones , Comprimidos , Equivalencia Terapéutica , Adulto JovenRESUMEN
BACKGROUND: Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS). OBJECTIVE: Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS. METHODS: Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo. RESULTS: Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions. CONCLUSIONS: CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00726648.
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Integrina alfa4/metabolismo , Integrina alfa4beta1/antagonistas & inhibidores , Esclerosis Múltiple/tratamiento farmacológico , Fenilalanina/análogos & derivados , Adulto , Método Doble Ciego , Esquema de Medicación , Femenino , Citometría de Flujo , Humanos , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Naftiridinas , Fenilalanina/administración & dosificación , Fenilalanina/farmacología , Recurrencia , Resultado del Tratamiento , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
PURPOSE: Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain. METHODS: A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs). RESULTS: Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions. DISCUSSION: The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.
Asunto(s)
Anticonvulsivantes/efectos adversos , Cognición/efectos de los fármacos , Lorazepam/efectos adversos , Piracetam/análogos & derivados , Pirrolidinonas/efectos adversos , Adolescente , Adulto , Recuento de Células Sanguíneas , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Estudios Cruzados , Método Doble Ciego , Electroencefalografía/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Femenino , Humanos , Levetiracetam , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Piracetam/efectos adversos , Tamaño de la Muestra , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. OBJECTIVE: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. METHODS: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters C(max), T(max), AUC0â(last), AUC0â(∞) and t(½) were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. RESULTS: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC(0-last) values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) µg · h/mL, respectively. Values for bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the tablet were 98.5% (95% CI, 89.7%-108.2%), 100.8% (95% CI, 91.4%-111.1%), and 87.1% (95% CI, 77.9%-97.5%). CONCLUSION: After delivery in the proximal small bowel, distal small bowel, or ascending colon, the systemic bioavailability of levetiracetam (AUC), but not C(max) and T(max), appeared comparable to that after oral administration and thus appeared site independent in this small group of healthy fasting men.
Asunto(s)
Anticonvulsivantes/farmacocinética , Colon Ascendente/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Intestino Delgado/metabolismo , Piracetam/análogos & derivados , Adolescente , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Disponibilidad Biológica , Cápsulas , Colon Ascendente/diagnóstico por imagen , Estudios Cruzados , Campos Electromagnéticos , Tránsito Gastrointestinal , Humanos , Absorción Intestinal , Intestino Delgado/diagnóstico por imagen , Levetiracetam , Masculino , Persona de Mediana Edad , Piracetam/administración & dosificación , Piracetam/sangre , Piracetam/farmacocinética , Cintigrafía , Comprimidos , Pentetato de Tecnecio Tc 99m , Adulto JovenRESUMEN
In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies.
Asunto(s)
Antialérgicos , Antiasmáticos , Hipersensibilidad/metabolismo , Modelos Biológicos , Adulto , Factores de Edad , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Antialérgicos/uso terapéutico , Antiasmáticos/farmacocinética , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/metabolismo , Peso Corporal/fisiología , Niño , Dieta , Humanos , Hipersensibilidad/tratamiento farmacológico , Modelos Estadísticos , Modelos EstructuralesRESUMEN
Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug-drug interactions have been explored across large adult and pediatric populations. The exposure-response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.
RESUMEN
PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Piracetam/análogos & derivados , Adolescente , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Carbamazepina/sangre , Carbamazepina/farmacocinética , Carbamazepina/uso terapéutico , Niño , Preescolar , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/sangre , Femenino , Fructosa/análogos & derivados , Fructosa/sangre , Fructosa/farmacocinética , Fructosa/uso terapéutico , Humanos , Lamotrigina , Levetiracetam , Masculino , Evaluación de Resultado en la Atención de Salud , Piracetam/sangre , Piracetam/farmacocinética , Piracetam/uso terapéutico , Placebos , Topiramato , Triazinas/sangre , Triazinas/farmacocinética , Triazinas/uso terapéutico , Ácido Valproico/sangre , Ácido Valproico/farmacocinética , Ácido Valproico/uso terapéuticoRESUMEN
PURPOSE: The primary objective of this placebo-controlled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics. METHODS: Single ascending doses of LEV administered by IV infusion (2,000, 3,000, 4,000 mg over 15 min; 1,500, 2,000, 2,500 mg over 5 min) were evaluated in 48 healthy subjects in a randomized, single-blind, placebo-controlled study. RESULTS: All randomized subjects completed the study. Adverse events reported after IV administration of LEV (Asunto(s)
Anticonvulsivantes/administración & dosificación
, Piracetam/análogos & derivados
, Administración Oral
, Adulto
, Anticonvulsivantes/efectos adversos
, Anticonvulsivantes/farmacocinética
, Área Bajo la Curva
, Presión Sanguínea/efectos de los fármacos
, Trastornos de Somnolencia Excesiva/inducido químicamente
, Mareo/inducido químicamente
, Relación Dosis-Respuesta a Droga
, Epilepsia/tratamiento farmacológico
, Fatiga/inducido químicamente
, Femenino
, Semivida
, Cefalea/inducido químicamente
, Frecuencia Cardíaca/efectos de los fármacos
, Humanos
, Infusiones Intravenosas
, Levetiracetam
, Masculino
, Piracetam/administración & dosificación
, Piracetam/efectos adversos
, Piracetam/farmacocinética
, Placebos
, Método Simple Ciego
, Factores de Tiempo
RESUMEN
BACKGROUND: Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible. OBJECTIVE: The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects. METHODS: This study consisted of 2 phases. Subjects entered the first phase, which was a single-dose, randomized, open-label, 2-way crossover bioavailability comparison of a 15-minute IV infusion of levetiracetam 1,500 mg and three 500-mg oral tablets. Subjects then entered the second phase, a multiple-dose, randomized, double-blind, placebo-controlled (2:1), parallel-group tolerability and pharmacokinetic study, in which they received 9 successive doses of levetiracetam 1,500 mg IV or placebo at 12-hour intervals. Plasma levetiracetam concentrations were determined by gas chromatography with nitrogen-phosphorus detection. The comparison of bioavailability was based on the 90% CIs around the geometric mean ratios for AUC and C(max) (IV/oral). RESULTS: Eighteen subjects (9 men, 9 women) participated in the study. All subjects were white. Their mean (SD) age was 35.0 (9.3) years, mean weight 73.3 (14.2) kg, and mean body mass index 23.9 (2.5) kg/m(2). After a single dose, the IV infusion and oral tablet were similar in terms of C(max) (50.5 and 47.7 microg/mL, respectively) and AUC (392.4 and 427.9 pg x h/mL). The geometric mean IV/oral ratios were 92.2 (90 % CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) for C(max) indicating that the IV and oral formulations were bioequivalent. After multiple twice-daily infusions, steady state was reached within 48 hours. Seventeen (94%) of 18 subjects had >or=1 treatment-emergent adverse event after single-dose administration. During the single-dose phase, the incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for the oral tablets; during the multiple-dose phase, the incidence of treatment-emergent adverse events was 67% (8/12) in the IV levetiracetam group and 33% (2/6) in the placebo group. The most common adverse events in the single-dose phase were somnolence (61% IV vs 28% oral) and postural dizziness (17% vs 39%, respectively). The most common adverse events with IV levetiracetam in the multiple-dose phase were also somnolence (33% vs 17% placebo) and postural dizziness (25% vs 0% placebo). CONCLUSIONS: In these healthy subjects, single doses of levetiracetam 1,500 mg administered as a 15-minute IV infusion and as oral tablets were bioequivalent. General and local tolerability during multiple dosing were good. Steady state was reached within 48 hours. Despite the limitations of a study of short duration and small size conducted in healthy subjects, the findings suggest that use of a 15-minute IV infusion of levetiracetam should be further investigated.