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Lecanemab (Leqembi®) was recently approved by health authorities in the United States, Japan, and China to treat early Alzheimer's disease (AD), including patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease upon confirmation of amyloid beta pathology. Extensively and sparsely sampled PK profiles from 1619 AD subjects and 21,929 serum lecanemab observations from two phase I, one phase II, and one phase III studies were well characterized using a two-compartment model with first-order elimination. The final PK model quantified covariate effects of body weight and sex on clearance and central volume of distribution, ADA-positive status, and albumin on clearance, and of Japanese ethnicity on central and peripheral volumes of distribution. Exposure to lecanemab was comparable between two lecanemab-manufacturing processes. However, none of the identified covariates in the model had a clinically relevant impact on model-predicted lecanemab Cmax or AUC at steady state following 10 mg/kg bi-weekly. Importantly, age, a well-recognized risk factor for AD, was not found to significantly affect lecanemab PK. The incidence of ARIA-E as a function of lecanemab exposure was modeled using a logit function with data pooled from 2641 subjects from the phase II and phase III studies, in which a total of 177 incidences of ARIA-E were observed. The probability of ARIA-E was significantly correlated with model-predicted Cmax and predicted to be higher in subjects homozygous for APOE4. The incidence of isolated ARIA-H was not associated with lecanemab exposure and was similar between placebo and lecanemab-treated subjects.
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BACKGROUND: This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aß) 42/Aß40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening. METHODS: Quantification of plasma pTau217R and Aß42/Aß40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts. RESULTS: Models integrating pTau217R outperformed Aß42/Aß40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R-based models for low amyloid levels reduced PET scans by 70.5% to 78.6%. DISCUSSION: pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aß42/Aß40's range. Combining it with plasma Aß42/Aß40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility. GOV IDENTIFIERS: NCT02956486 (MissionAD1), NCT03036280 (MissionAD2), NCT04468659 (AHEAD3-45), NCT03887455 (ClarityAD) HIGHLIGHTS: Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid-PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aß42/Aß40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This model identifies subjects above or below various CL thresholds with high accuracy. pTau217R-based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Tomografía de Emisión de Positrones , Proteínas tau , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Cohortes , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Ensayos Clínicos como AsuntoRESUMEN
INTRODUCTION: Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß species (protofibrils) with activity at amyloid plaques. Amyloid-related imaging abnormalities (ARIA) profiles appear to differ for various anti-amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer's disease. METHODS: Study 201 trial was double-blind, placebo-controlled (core) with an open-label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan-Meier graphs. An exposure response model was developed. RESULTS: In the phase 2 core and OLE, there was a low incidence of ARIA-E (<10%), with <3% symptomatic cases. ARIA-E was generally asymptomatic, mild-to-moderate in severity, and occurred early (<3 months). ARIA-E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA-H and ARIA-E occurred with similar frequency in core and OLE. DISCUSSION: Lecanemab can be administered without titration with modest incidence of ARIA.
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OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Estudios Transversales , Proteínas tau/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones/métodos , Atrofia/patología , Biomarcadores/líquido cefalorraquídeo , Progresión de la Enfermedad , Microtúbulos/metabolismo , Microtúbulos/patologíaRESUMEN
Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Farmacología en Red , Péptidos beta-Amiloides , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores , Fragmentos de Péptidos , Tomografía de Emisión de PositronesRESUMEN
This report describes polysomnography and sleep diary exposure-response analyses from Study E2006-G000-304 (Study 304), a 1-month trial of 5- or 10-mg lemborexant, zolpidem, or placebo; and Study E2006-G000-303 (Study 303), a 6-month trial of 5- or 10-mg lemborexant or placebo. Studies 304 and 303 included 1006 (86%) and 956 (68%) (female) participants, respectively; >40% were ≥65 years, with individual lemborexant exposures derived from a previously described pharmacokinetic model. Linear mixed-effects analyses of polysomnography: latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) quantified the change from baseline given lemborexant exposure, time, and covariates, guided by consensus recommendations regarding clinical significance. A small impact of sex, body weight, and race was predicted for LPS and SE, irrespective of treatment. Effect of age on LPS was small; baseline SE was estimated to be 8% higher for a 50-year-old versus an 80-year-old, decreasing to 6% by 1 month. Baseline WASO was 13 minutes longer for Black versus White subjects, corresponding to a 5-minute lower change from baseline at the end of the study. For subjective end points, the statistically significant covariate effects for age, sex, and race were not deemed therapeutically relevant, likely reflecting physiologic sleep pattern changes across age and study subgroups. Both polysomnography and subjective analyses indicated clinically meaningful differences from baseline for both lemborexant treatments, with effects being greater for 10-mg versus 5-mg lemborexant, while indicating that covariate-specific lemborexant dose adjustments are not warranted.
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Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Antagonistas de los Receptores de Orexina , Polisomnografía , Lipopolisacáridos/farmacología , Método Doble Ciego , SueñoRESUMEN
BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).
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Enfermedad de Alzheimer , Anticuerpos Monoclonales Humanizados , Nootrópicos , Humanos , Actividades Cotidianas , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Cognición/efectos de los fármacos , Método Doble Ciego , Nootrópicos/efectos adversos , Nootrópicos/farmacología , Nootrópicos/uso terapéuticoRESUMEN
BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aß species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). RESULTS: At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aß42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aß42/40 ratio, and reductions in plasma p-tau181. CONCLUSIONS: Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01767311 .
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/diagnóstico por imagen , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Proteínas Amiloidogénicas , Cognición , Péptidos beta-AmiloidesRESUMEN
Lecanemab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aß aggregate species, while demonstrating low affinity for Aß monomer. This article describes the population pharmacokinetic (PK) and PK/pharmacodynamic (PD) analyses for amyloid plaques, as measured using positron emission tomography (PET), and biomarkers of amyloid pathology as evidenced by Aß42/40 ratio and plasma p-tau181 following i.v. administration of lecanemab in subjects with early Alzheimer's disease. Lecanemab PKs were well-characterized with a two-compartment model with first-order elimination. Final PK model contained covariate effects of anti-drug antibody positive status, sex, body weight, and albumin on clearance. The time course of amyloid PET standard uptake ratio (SUVr), plasma Aß42/40 ratio, and p-tau181 were described using indirect response models with lecanemab exposure as a maximum effect function stimulating the reduction of SUVr, and as a linear function increasing Aß42/40 ratio and decreasing p-tau181 formation rates. PK/PD simulations show that 10 mg/kg biweekly dosing results in larger and faster decrease in SUVr and p-tau181 and increase in Aß42/40 ratio as compared to 10 mg/kg monthly dose. Furthermore, the PK/PD simulations showed that after treatment discontinuation the brain amyloid re-accumulation to baseline levels is slow with a recovery half-life of ~4 years, whereas plasma Aß42/40 ratio and p-tau181 return to baseline levels faster than amyloid. Given the relationship between changes in amyloid PET SUVr and soluble biomarkers, the developed PK/PD models can be used to inform lecanemab dose regimens in future clinical studies.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Fragmentos de Péptidos , Tomografía de Emisión de Positrones/métodos , BiomarcadoresRESUMEN
BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. METHODS: Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. RESULTS: E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. CONCLUSIONS: S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.
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Enfermedad por Cuerpos de Lewy , Inhibidores de Fosfodiesterasa , Anciano , Área Bajo la Curva , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Guanosina Monofosfato , Voluntarios Sanos , Humanos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster FosfóricasRESUMEN
PURPOSE/BACKGROUND: As part of a human abuse potential (HAP) study of lemborexant (LEM), the effects of therapeutic (LEM 10 mg), and supratherapeutic doses of LEM 20 mg and LEM 30 mg on cognition and psychomotor performance were compared with placebo (PBO) and supratherapeutic doses of zolpidem (ZOL) 30 mg and suvorexant (SUV) 40 mg. Subjects (n = 32) were healthy, nondependent, recreational sedative users able to discriminate the effects of both SUV and ZOL from PBO on subjective drug measures. METHODS/PROCEDURES: The human abuse potential study was a single-dose, randomized, double-blind, PBO-controlled, 6-way crossover study. Eligible subjects admitted to the treatment phase completed the choice reaction test (CRT) and divided attention test. The CRT included measurements of recognition reaction time (RRT) and motor reaction time. FINDINGS/RESULTS: Recognition reaction time and mean maximum change from baseline (CFB max ) scores were significantly increased (slower performance) versus PBO for all LEM doses (all P < 0.001), ZOL ( P < 0.001), and SUV ( P = 0.004), and LEM (all doses) was not statistically different from ZOL or SUV. Motor reaction time and mean CFB max versus PBO were significantly increased for all LEM doses (all P < 0.001), and ZOL ( P < 0.001) and SUV ( P < 0.001). All LEM doses showed significantly decreased (better performance) mean CFB max versus ZOL (all P < 0.001), but not SUV. Notably, all cognitive effects in the CRT and divided attention test were limited to the main treatment phase (up to 8 hours postdose). IMPLICATIONS/CONCLUSIONS: All active doses of LEM, ZOL, and SUV generally increased reaction time and reduced divided attention capabilities versus PBO. However, at therapeutic/supratherapeutic doses, LEM led to significantly less cognitive impairment than supratherapeutic doses of ZOL in some measures.
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Hipnóticos y Sedantes , Antagonistas de los Receptores de Orexina , Azepinas , Cognición , Estudios Cruzados , Método Doble Ciego , Humanos , Hipnóticos y Sedantes/efectos adversos , Antagonistas de los Receptores de Orexina/efectos adversos , Piridinas , Pirimidinas , Triazoles , ZolpidemRESUMEN
BACKGROUND: Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries. PROCEDURES: This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase. RESULTS: Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the "at this moment" drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO ( P > 0.05) but not different compared with ZOL or SUV. CONCLUSIONS: For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.
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Hipnóticos y Sedantes , Antagonistas de los Receptores de Orexina , Adulto , Azepinas , Estudios Cruzados , Método Doble Ciego , Humanos , Hipnóticos y Sedantes/efectos adversos , Antagonistas de los Receptores de Orexina/efectos adversos , Piridinas , Pirimidinas , Triazoles , Zolpidem/efectos adversosRESUMEN
The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development. In this review, five examples from different sponsors are shared in which C-QTc analysis was performed on data from FIH studies. Case 1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case 2 C-QTc analysis of FIH data was performed prior to full pharmacokinetic characterization in patients, and the role of nonclinical assays in an integrated risk assessment is discussed. Case 3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case 4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case 5 highlights an approach to perform a preliminary C-QTc analysis early in development and postpone the definitive analysis until proof of efficacy is demonstrated. The strategy of collecting and storing ECG data from FIH studies to enable an informed decision on whether and when to apply C-QTc analysis to obviate the need for a TQT study is described.
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Síndrome de QT Prolongado , Farmacología Clínica , Humanos , Síndrome de QT Prolongado/inducido químicamente , Electrocardiografía , Medición de RiesgoRESUMEN
Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (Cmax ) values were 1.35- to 1.61-fold higher than Cmax . Simulated plasma concentration-time profiles using pooled pharmacokinetic data further supported oral and IV perampanel interchangeability in two scenarios: 12-mg per day IV dosing during a temporary 7-day switch from oral steady-state maintenance therapy, and treatment initiation with 2-mg perampanel. Thirty-four (70.8%) subjects experienced treatment-related adverse events. The IV perampanel safety profile was similar to that of oral perampanel without new safety concerns. Perampanel IV infusions may be a suitable temporary alternative to oral perampanel for treatment maintenance and/or initiation.
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Nitrilos , Piridonas , Área Bajo la Curva , Estudios Cruzados , Humanos , Nitrilos/efectos adversos , Piridonas/efectos adversosRESUMEN
BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. PATIENTS AND METHODS: A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. RESULTS: A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of â¼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. CONCLUSION: This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.
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Enfermedad por Cuerpos de Lewy , Síndrome de QT Prolongado , Inhibidores de Fosfodiesterasa , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Humanos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Síndrome de QT Prolongado/inducido químicamente , Inhibidores de Fosfodiesterasa/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan. AIMS: This study was conducted to investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant. METHODS: This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory. RESULTS: Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment-emergent adverse event was somnolence. CONCLUSION: Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant.
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Antagonistas de los Receptores de Orexina , Piridinas , Adulto , Estudios Cruzados , Etanol/efectos adversos , Femenino , Humanos , Masculino , Antagonistas de los Receptores de Orexina/efectos adversos , Antagonistas de los Receptores de Orexina/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacologíaRESUMEN
Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.
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Etinilestradiol/administración & dosificación , Noretindrona/administración & dosificación , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Adolescente , Adulto , Área Bajo la Curva , Anticonceptivos Orales Combinados/administración & dosificación , Anticonceptivos Orales Combinados/farmacocinética , Anticonceptivos Orales Combinados/farmacología , Interacciones Farmacológicas , Etinilestradiol/farmacocinética , Etinilestradiol/farmacología , Femenino , Humanos , Noretindrona/farmacocinética , Noretindrona/farmacología , Antagonistas de los Receptores de Orexina/administración & dosificación , Antagonistas de los Receptores de Orexina/farmacocinética , Antagonistas de los Receptores de Orexina/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Adulto JovenRESUMEN
Poor adherence to anti-seizure medications (ASMs) is associated with breakthrough seizures and potentially increased toxicity in patients with epilepsy. Extended-release (ER) drugs and immediate-release (IR) drugs with a long half-life (t1/2) that permit once-daily dosing (such as, perampanel, zonisamide, lamotrigine [IR, ER] and topiramate [ER]) have a number of advantages over short t1/2 ASMs that require multiple daily dosing. These advantages include simplification of dosing regimens, reduction in pill burden, and a decrease in the peak-to-trough fluctuations in serum drug concentration that may be associated with a decreased risk of adverse effects and seizures. Such properties have wider implications in improving patient adherence to treatment. This article is intended as a practical guide for clinicians that provides an overview of the features of ER ASMs and long t1/2 IR ASMs that are advantageous in the context of patient adherence and pharmacokinetic "forgiveness" (after missing a dose). In addition, we note that efforts to improve adherence should not depend solely on drug dosing regimens and drug pharmacokinetics, but should be part of a wider strategy that includes therapeutic drug monitoring, improved healthcare provider-patient dialogue, patient education, and the use of "reminder" technology.
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Epilepsia , Anticonvulsivantes/uso terapéutico , Preparaciones de Acción Retardada , Epilepsia/tratamiento farmacológico , Semivida , Humanos , Lamotrigina/uso terapéutico , Topiramato/uso terapéuticoRESUMEN
Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open-label, parallel-group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) HI and healthy age-, sex-, and body mass index (BMI)-matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax ] and area under the curve extrapolated to infinity [AUC0-inf ]) increased by ~58% (Cmax ) and ~25% (AUC0-inf ) in subjects with mild HI and ~22% (Cmax ) and ~54% (AUC0-inf ) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060-0.065). All treatment-emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups.