Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 84
Filtrar
1.
Natl Med J India ; 37(3): 155-161, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39448540

RESUMEN

Vasant Ramji Khanolkar was the first Indian pathologist and a pioneering researcher who was at the forefront of the diverse fields of cancer research, blood group genetics, epidemiology and leprosy research, etc. in the mid-twentieth century. All his cutting-edge research took place after he joined Tata Memorial Hospital, Bombay (now Mumbai), as Director of Laboratories. There is little evidence of his research in the first 17 years of his career in India, at J.J. Hospital and K.E.M. Hospital, Bombay. We tried to address this gap by attempting to obtain information on Khanolkar's papers from PubMed, prior to his having joined Tata Memorial Hospital. We evaluated the abstracts of the presentations that he made at the meetings of the Teaching Pathologists Association, Bombay. Finally, we extracted from the autopsy registers at the two hospitals, any useful information about the autopsies that he had performed. Khanolkar performed preliminary laboratory research in anaemia as well as some experimental pathology in his stint at K.E.M. Hospital. Further, surprisingly, histology was not performed on most autopsies at J.J. Hospital for the period that he was Professor, but was done at K.E.M. Hospital. Why Khanolkar was a late bloomer and did not perform much research or publish in the first two institutions that he was Professor at, remains a mystery.


Asunto(s)
Patólogos , India , Historia del Siglo XX , Humanos , Patólogos/historia , Patología/historia , Investigación Biomédica/historia , Autopsia/historia , Investigadores/historia
2.
Br J Clin Pharmacol ; 2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39112438

RESUMEN

AIMS: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody that was first approved by the United States (US) Food and Drug Administration (FDA) for the treatment of allergic asthma in 2003. The pivotal trials supporting the initial approval of omalizumab used dosing determined by patient's baseline IgE and body weight, with the goal of reducing the mean free IgE level to approximately 25 ng/mL or less. While the underlying parameters supporting the dosing table remained the same, subsequent studies and analyses have resulted in approved alternative versions of the dosing table, including the European Union (EU) asthma dosing table, which differs in weight bands and maximum allowable baseline IgE and omalizumab dose. In this study, we leveraged modelling and simulation approaches to predict and compare the free IgE reduction and forced expiratory volume in 1 second (FEV1) improvement with omalizumab dosing based on the US and EU asthma dosing tables. METHODS: Previously established population pharmacokinetic-IgE and IgE-FEV1 models were used to predict and compare post-treatment free IgE and FEV1 based on the US and EU dosing tables. Clinical trial simulations (with virtual asthma populations) and Monte Carlo simulations were performed to provide both breadth and depth in the comparisons. RESULTS: The US and EU asthma dosing tables were predicted to result in generally comparable free IgE suppression and FEV1 improvement. CONCLUSIONS: Despite the similar free IgE and FEV1 outcomes from simulations, this has not been clinically validated with respect to the registrational endpoint of reduction in annualized asthma exacerbations.

4.
5.
Pharm Dev Technol ; 28(7): 678-696, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37427544

RESUMEN

Evolving therapeutic landscape through combinatorial chemistry and high throughput screening have resulted in an increased number of poorly soluble drugs. Drug delivery strategies quickly adapted to convert these drugs into successful therapies. Amorphous solid dispersion (ASD) technology is widely employed as a drug delivery strategy by pharmaceutical industries to overcome the challenges associated with these poorly soluble drugs. The development of ASD formulation requires an understanding of polymers and manufacturing techniques. A review of US FDA-approved ASD-based products revealed that only a limited number of polymers and manufacturing technologies are employed by pharmaceutical industries. This review provides a comprehensive guide for the selection and overview of polymers and manufacturing technologies adopted by pharmaceutical industries for ASD formulation. The various employed polymers with their underlying mechanisms for solution-state and solid-state stability are discussed. ASD manufacturing techniques, primarily implemented by pharmaceutical industries for commercialization, are presented in Quality by Design (QbD) format. An overview of novel excipients and progress in manufacturing technologies are also discussed. This review provides insights to the researchers on the industrially accepted polymers and manufacturing technology for ASD formulation that has translated these challenging drugs into successful therapies.


Asunto(s)
Química Farmacéutica , Polímeros , Composición de Medicamentos/métodos , Química Farmacéutica/métodos , Solubilidad , Preparaciones Farmacéuticas , Excipientes
6.
Eur J Pharm Sci ; 182: 106380, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36638898

RESUMEN

Quantitative systems pharmacology (QSP) models are an important facet of pharmaceutical and clinical research as they combine mechanistic models of physiology in health and disease with pharmacokinetics/pharmacodynamics to predict systems-level effects. The quantitative clinical pharmacology toolbox has traditionally included both mechanistic modeling and population approaches, collectively called pharmacometrics, but the current landscape requires the optimization and use of multiple models together. Here, we explore several case studies in drug development that exemplify three approaches for using QSP and pharmacometrics models together - parallel synchronization, cross-informative use, and sequential integration. While these approaches are increasingly applied in drug development, achieving a true convergence of QSP and pharmacometrics that fully exploits their synergy will require new tools and methods that enable greater technical integration, in addition to nurturing scientists with diverse modeling expertise that enable cross-discipline strategy. Extensions of existing methods used in each approach as well as additional resources including machine learning models, data-at-scale, end-to-end computation platforms, and real-time analytics will enable this convergence.


Asunto(s)
Farmacología en Red , Farmacología Clínica , Desarrollo de Medicamentos , Investigación , Preparaciones Farmacéuticas , Modelos Biológicos
7.
Hum Vaccin Immunother ; 18(5): 2078626, 2022 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-35853188

RESUMEN

Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.


Asunto(s)
Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Adulto , Anticuerpos Antivirales , Estudios Clínicos como Asunto , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Humanos , Inmunogenicidad Vacunal , Masculino , Persona de Mediana Edad , Papillomaviridae , Infecciones por Papillomavirus/prevención & control , Vacunas Combinadas
8.
Clin Transl Sci ; 15(1): 130-140, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34432389

RESUMEN

Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti-drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti-PD-L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13-54%) developed treatment-emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA-positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure-response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.


Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/metabolismo , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Farmacología Clínica , Ensayos Clínicos como Asunto , Humanos , Neoplasias/tratamiento farmacológico
9.
Br J Clin Pharmacol ; 87(6): 2493-2501, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33217012

RESUMEN

Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on 3 different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (i) Cox-proportional hazards modelling and case-matching; (ii) tumour growth inhibition-overall survival modelling; and (iii) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programmes. Therefore, the strengths and weaknesses of the other 2 approaches are considered, and the favourable utility of tumour growth inhibition-overall survival modelling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials and proposes that development programmes be designed to study more dose levels in earlier trials.


Asunto(s)
Antineoplásicos Inmunológicos , Neoplasias , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Desarrollo de Medicamentos , Humanos , Oncología Médica , Neoplasias/tratamiento farmacológico
11.
Contemp Clin Trials ; 92: 105996, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32247041

RESUMEN

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.


Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Infecciones por Papillomavirus/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Infecciones por Papillomavirus/virología , Vigilancia de Productos Comercializados , Sistema de Registros , Países Escandinavos y Nórdicos , Neoplasias del Cuello Uterino/virología , Adulto Joven
12.
Colloids Surf B Biointerfaces ; 186: 110736, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31865121

RESUMEN

This study reports a detailed characterization of a nonionic microemulsion (µE) composed of n-butylacetate/α-tocopheryl polyethylene glycol succinate (TPGS)/alcohol/water. Two approaches of expanding the monophasic area were explored; (i) addition of Pluronic® 123 (P123) in aqueous phase, and (ii) use of short chain alcohol (CnHn+1OH; n = 2-4) as cosurfactant. Pseudo-ternary phase diagrams were constructed using water titration method. Characterizations were performed using dynamic light scattering (DLS), differential scanning calorimetry (DSC), small angle neutron scattering (SANS) and electron microscopic techniques. DSC and SANS results showed gradual structural transformation from water-in-oil to oil-in-water system. The optimized formulation (oil/Smix/water - 19/40/41) showed average hydrodynamic diameter of 22 nm, consistent with electron microscopic observations. Ethanol (EtOH), with its high fluidity and smaller headgroup area, offered maximum expansion in the phase boundary. Surfactant unimers, derived from EtOH-driven de-micellization, reinforced the interface and solubilized the incoming oil molecules. Oil incorporation was accompanied with improved loading of carbamazepine, a hydrophobic drug. Except marginal swelling, no significant microstructural changes were noticed during water dilution (≈90%) and salt addition (0.9% NaCl) in the optimized µE formulation. A linear increase in oil incorporation was noticed upon adding propylene glycol as a cosolvent.


Asunto(s)
Tensoactivos/química , Agua/química , Emulsiones/química , Etanol/química , Estructura Molecular , Tamaño de la Partícula , Transición de Fase , Poloxaleno/química , Polietilenglicoles/química , Solubilidad , Succinatos/química , Propiedades de Superficie , alfa-Tocoferol/química
13.
PLoS One ; 14(3): e0212837, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30913226

RESUMEN

BACKGROUND: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01716234.


Asunto(s)
Antifúngicos/farmacocinética , Área Bajo la Curva , Huésped Inmunocomprometido , Triazoles/farmacocinética , Administración Oral , Adolescente , Factores de Edad , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antineoplásicos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Lactante , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/inmunología , Infecciones Fúngicas Invasoras/prevención & control , Masculino , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Neutropenia/complicaciones , Neutropenia/inmunología , Estudios Prospectivos , Triazoles/administración & dosificación , Triazoles/efectos adversos
14.
Bioinformatics ; 35(2): 235-242, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29985971

RESUMEN

Motivation: Kinases play a significant role in diverse disease signaling pathways and understanding kinase inhibitor selectivity, the tendency of drugs to bind to off-targets, remains a top priority for kinase inhibitor design and clinical safety assessment. Traditional approaches for kinase selectivity analysis using biochemical activity and binding assays are useful but can be costly and are often limited by the kinases that are available. On the other hand, current computational kinase selectivity prediction methods are computational intensive and can rarely achieve sufficient accuracy for large-scale kinome wide inhibitor selectivity profiling. Results: Here, we present a KinomeFEATURE database for kinase binding site similarity search by comparing protein microenvironments characterized using diverse physiochemical descriptors. Initial selectivity prediction of 15 known kinase inhibitors achieved an >90% accuracy and demonstrated improved performance in comparison to commonly used kinase inhibitor selectivity prediction methods. Additional kinase ATP binding site similarity assessment (120 binding sites) identified 55 kinases with significant promiscuity and revealed unexpected inhibitor cross-activities between PKR and FGFR2 kinases. Kinome-wide selectivity profiling of 11 kinase drug candidates predicted novel as well as experimentally validated off-targets and suggested structural mechanisms of kinase cross-activities. Our study demonstrated potential utilities of our approach for large-scale kinase inhibitor selectivity profiling that could contribute to kinase drug development and safety assessment. Availability and implementation: The KinomeFEATURE database and the associated scripts for performing kinase pocket similarity search can be downloaded from the Stanford SimTK website (https://simtk.org/projects/kdb). Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Sitios de Unión , Biología Computacional , Bases de Datos de Proteínas , Desarrollo de Medicamentos , Inhibidores de Proteínas Quinasas/química , Unión Proteica , Transducción de Señal
15.
Hum Vaccin Immunother ; 15(1): 141-145, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30261146

RESUMEN

BACKGROUND: This exploratory analysis was conducted to characterize the level of HPV types 6/11 antibodies in peripartum maternal blood and in cord blood of infants born to women who received 9-valent HPV (9vHPV) vaccine or quadrivalent HPV (qHPV) vaccine in a pivotal efficacy study (V503-001, NCT 00543543). METHODS: A total of 21 mother-infant pairs had evaluable HPV 6/11 results available for analysis. HPV6/11 antibodies were assessed using competitive Luminex immunoassay. The distribution of the ratios of infant to mother anti-HPV antibodies (i.e., infant-anti-HPV/mother- anti-HPV) was summarized. RESULTS: All mothers and infants were seropositive to HPV 6 and HPV 11. Anti-HPV 6/11 geometric mean titers (GMTs) in peripartum maternal blood and in cord blood of infant born to study participants were highly correlated. A 100% of infants born to seropositive mothers were also seropositive. The GMT ratios of peripartum maternal blood vs. those in cord blood were HPV 6: 1.23 [0.43, 3.49] and HPV 11: 1.29 [0.54, 3.07] in the 9vHPV vaccine group and HPV 6: 1.33 [0.41, 4.29] and HPV 11: 1.19 [0.45, 3.13] in the qHPV vaccine group, respectively. CONCLUSIONS: These results indicate that antibodies induced by the 9vHPV vaccine cross the placenta, which could potentially be beneficial against HPV6/11 infection and related disease such as recurrent respiratory papillomatosis.


Asunto(s)
Anticuerpos Antihepatitis/sangre , Papillomavirus Humano 11/inmunología , Papillomavirus Humano 6/inmunología , Inmunidad Materno-Adquirida , Vacunas contra Papillomavirus/inmunología , Adolescente , Adulto , Método Doble Ciego , Femenino , Sangre Fetal/inmunología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Humanos , Inmunogenicidad Vacunal , Lactante , Madres , Vacunas contra Papillomavirus/administración & dosificación , Embarazo , Adulto Joven
16.
Indian J Surg Oncol ; 9(4): 598-600, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30538397

RESUMEN

Granular cell tumours are uncommon, usually benign soft tissue tumours. They are thought to be neural, arising from Schwann cells and can occur at various sites. Their occurrence in gastrointestinal tract is rare, the commonest site being oesophagus followed by large intestine. Gastric localization is unusual. A young female presented with abdominal discomfort since 3 months. Endoscopy showed a nodule in the body of stomach. Biopsy revealed features of granular cell tumour on microscopy, which was confirmed by immunohistochemical positivity for S100 and CD68. Wide excision of the tumour was performed. At the 6-month follow-up, patient was asymptomatic. The diagnosis of gastric granular cell tumour is based on endoscopic biopsy. Unless there is histological evidence of malignancy, wide local excision is an adequate surgical treatment.

17.
Hum Vaccin Immunother ; 14(12): 2916-2920, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30024827

RESUMEN

BACKGROUND: ZOSTAVAX (ZVL; Zoster Virus Live), is a single dose, live, attenuated vaccine licensed for the prevention of herpes zoster (HZ) and post herpetic neuralgia (PHN) in adults ≥50 years of age. Injection site adverse events (AEs) of erythema, swelling and pain were solicited within 5 days post vaccination in the 2 pivotal studies of ZVL; ZEST (ZOSTAVAX Efficacy and Safety Trial) and SPS (Shingles Prevention Study). Protocol specified criteria were used to report the frequency and intensity of injection site AEs in ZEST and SPS studies. Subsequently, the FDA Toxicity Grading Scale provided guidance for uniform assessment of AEs across all adult vaccine clinical trials. The objective of this post-hoc analysis was to categorize the previously reported injection site AEs in two pivotal trials of ZVL according to the current FDA Toxicity Grading Scale. METHODS: The current FDA Toxicity Grading Scale provides a measure for classifying injection site AEs by four grades [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe) and Grade 4 (life threatening)]. Injection site erythema, swelling, and pain intensity gradings were assigned to the respective FDA Toxicity Grade based on this appropriation. A descriptive analysis of the proportion and risk difference (within 95% confidence intervals) of injection site AEs per the FDA Toxicity Grading Scale is provided. RESULTS: The frequency of injection site AEs (erythema, swelling, pain) after subcutaneous vaccination with ZVL were higher in recipients of ZVL compared with placebo. Majority of the injection site AEs observed were Grade 1 (mild) or Grade 2 (moderate) in intensity. Additionally, Grade 3 (severe) injection site AEs were observed infrequently. CONCLUSIONS: Application of the FDA Toxicity Grading Scale provides a uniform AE assessment tool across different adult vaccines. This post hoc summary of injection site AEs using FDA Toxicity Grading Scale provides further evidence of low frequency of severe injection site AEs post ZVL vaccination.


Asunto(s)
Vacuna contra el Herpes Zóster/administración & dosificación , Vacuna contra el Herpes Zóster/efectos adversos , Inmunización/efectos adversos , Reacción en el Punto de Inyección/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Anciano , Edema/inducido químicamente , Eritema/inducido químicamente , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/normas , Herpesvirus Humano 3 , Humanos , Inmunización/normas , Reacción en el Punto de Inyección/fisiopatología , Inyecciones/métodos , Inyecciones/normas , Persona de Mediana Edad , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/fisiopatología , Dolor/inducido químicamente , Estados Unidos , United States Food and Drug Administration , Vacunación/efectos adversos , Vacunación/normas
18.
Clin Cancer Res ; 24(14): 3292-3298, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29685883

RESUMEN

Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the predictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non-small cell lung cancer.Patients and Methods: OS benefit with atezolizumab versus docetaxel was observed in both POPLAR (phase II) and OAK (phase III), although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks.Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and number of metastatic sites as independent prognostic factors and estimated KG, predicted OS HR in subpopulations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval), 0.73 (0.63-0.85), versus 0.73 observed. The POPLAR OS model predicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS.Conclusions: KG has potential as a model-based early endpoint to inform decisions in cancer immunotherapy studies. Clin Cancer Res; 24(14); 3292-8. ©2018 AACR.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Modelos Teóricos , Algoritmos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Humanos , Neoplasias Pulmonares/diagnóstico , Terapia Molecular Dirigida , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Carga Tumoral
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA