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1.
JAMA ; 323(3): 256-267, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961417

RESUMO

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.


Assuntos
Propiofenonas/sangue , Absorção Cutânea , Protetores Solares/farmacocinética , Acrilatos/sangue , Acrilatos/farmacocinética , Adulto , Benzofenonas/sangue , Benzofenonas/farmacocinética , Cinamatos/sangue , Cinamatos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propiofenonas/farmacocinética , Salicilatos/sangue , Salicilatos/farmacocinética , Protetores Solares/efeitos adversos
2.
CPT Pharmacometrics Syst Pharmacol ; 9(1): 21-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31652029

RESUMO

The use of computational models in drug development has grown during the past decade. These model-informed drug development (MIDD) approaches can inform a variety of drug development and regulatory decisions. When used for regulatory decision making, it is important to establish that the model is credible for its intended use. Currently, there is no consensus on how to establish and assess model credibility, including the selection of appropriate verification and validation activities. In this article, we apply a risk-informed credibility assessment framework to physiologically-based pharmacokinetic modeling and simulation and hypothesize this evidentiary framework may also be useful for evaluating other MIDD approaches. We seek to stimulate a scientific discussion around this framework as a potential starting point for uniform assessment of model credibility across MIDD. Ultimately, an overarching framework may help to standardize regulatory evaluation across therapeutic products (i.e., drugs and medical devices).

5.
JAMA ; 321(21): 2082-2091, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31058986

RESUMO

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.


Assuntos
Absorção Cutânea , Protetores Solares/farmacocinética , Acrilatos/sangue , Acrilatos/farmacocinética , Adulto , Benzofenonas/sangue , Benzofenonas/farmacocinética , /farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Concentração Máxima Permitida , Projetos Piloto , Propiofenonas/sangue , Propiofenonas/farmacocinética , Creme para a Pele , Ácidos Sulfônicos/sangue , Ácidos Sulfônicos/farmacocinética , Protetores Solares/administração & dosagem , Protetores Solares/análise
6.
Clin Pharmacol Ther ; 105(4): 943-953, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30447156

RESUMO

Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.


Assuntos
Biomarcadores/metabolismo , Eletrocardiografia/efeitos dos fármacos , Canais Iônicos/antagonistas & inibidores , Moduladores de Transporte de Membrana/uso terapêutico , Preparações Farmacêuticas/administração & dosagem , Adulto , Estudos Cross-Over , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Torsades de Pointes/tratamento farmacológico , Torsades de Pointes/metabolismo
7.
Clin Pharmacol Ther ; 105(3): 710-718, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30350311

RESUMO

We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once-daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria. We hypothesized that the lack of control on urinary calcium excretion was due to the short half-life of PTH. The QSP model-based simulations indicated that a more frequent dosing regimen may provide better control on hypercalciuria while maintaining normocalcemia. A postmarketing trial was recommended to assess pharmacokinetics (PKs) and pharmacodynamics (PDs) of PTH dose and dosing regimen. Although other modeling approaches may be feasible, in this specific case, QSP model-based simulations fulfilled the information gap to support recommendations of this postmarketing trial.


Assuntos
Hipoparatireoidismo/tratamento farmacológico , Modelos Biológicos , Hormônio Paratireóideo/administração & dosagem , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Hipoparatireoidismo/metabolismo , Hormônio Paratireóideo/metabolismo
8.
Pharmacotherapy ; 38(9): 899-906, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29920722

RESUMO

INTRODUCTION: A target international normalized ratio (INR) of 2-3 has been recommended for patients with atrial fibrillation (AF) and risk factors for thromboembolism. This recommendation is largely based on evidence from observational studies a decade ago. This study utilized collective data from modern trials with warfarin controls to examine the relationship of warfarin anticoagulation, as assessed by INR, on the clinical outcome events of interest. METHODS: Data on warfarin-treated patients from three clinical studies supporting the approval of dabigatran (Pradaxa), apixaban (Eliquis), and edoxaban (Savaysa) were pooled. Ischemic stroke, intracranial hemorrhage (ICH), and all-cause death were selected as the outcome events of interest. Multivariate Cox regression modeling was performed to examine the association between time-dependent INR and each outcome event. Benefit-risk assessment was evaluated by summing the estimated annual event rate for ischemic stroke and ICH. RESULTS: A total of 21,883 patients representing 322 ischemic strokes, 288 ICHs, and 657 all-cause deaths were included in the analysis. The models used suggest that the risk of ischemic stroke is greatly reduced when INR exceeds 2; in contrast, the risk of ICH increases monotonically as INR increases. When combining ischemic stroke and ICH events, the lowest estimated annual event rate was observed between INR of 2 and 2.5; the risk only slightly increased between INR of 1.8 and 3.0. Similarly, a U-shaped relationship between INR and the risk of all-cause death was found. CONCLUSIONS: This study using collective warfarin data from recent large prospective trials indicates that INR between 2 and 2.5 provides the best balance between ischemic stroke and ICH, as well as optimal protection against death in patients with AF.


Assuntos
Fibrilação Atrial/mortalidade , Coeficiente Internacional Normatizado/normas , Hemorragias Intracranianas/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Varfarina/uso terapêutico , Idoso , Fibrilação Atrial/tratamento farmacológico , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estados Unidos/epidemiologia
9.
Am Heart J ; 199: 59-67, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29754667

RESUMO

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Anticoagulantes/farmacocinética , Fibrilação Atrial/complicações , Fibrilação Atrial/metabolismo , Relação Dose-Resposta a Droga , Humanos , Acidente Vascular Cerebral/metabolismo
11.
J Clin Pharmacol ; 56(11): 1326-1334, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27040726

RESUMO

During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.


Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/administração & dosagem , United States Food and Drug Administration , Adulto , Fatores Etários , Criança , Ensaios Clínicos como Assunto/métodos , Relação Dose-Resposta a Droga , Descoberta de Drogas/tendências , Humanos , Preparações Farmacêuticas/metabolismo , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/tendências
12.
Drug Metab Dispos ; 44(7): 924-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27079249

RESUMO

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.


Assuntos
Aprovação de Drogas , Cálculos da Dosagem de Medicamento , Rotulagem de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Adalimumab/administração & dosagem , Adalimumab/farmacocinética , Adolescente , Desenvolvimento do Adolescente , Adulto , Fatores Etários , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Criança , Desenvolvimento Infantil , Pré-Escolar , Doença de Crohn/tratamento farmacológico , Relação Dose-Resposta a Droga , Esomeprazol/administração & dosagem , Esomeprazol/farmacocinética , Refluxo Gastroesofágico/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Modelos Biológicos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacocinética , Convulsões/tratamento farmacológico , Vigabatrina/administração & dosagem , Vigabatrina/farmacocinética
13.
J Electrocardiol ; 48(4): 533-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25796102

RESUMO

INTRODUCTION: The electrocardiographic index Tpeak-Tend has been proposed as a marker of dispersion of repolarization and may be a stronger predictor of torsade de pointes risk than QTc prolongation. METHODS AND RESULTS: We assessed whether quinidine-induced Tpeak-Tend prolongation is greater in women than men. The relationship between QTc prolongation and quinidine concentration was greater in women than men (38 ± 10 vs. 28 ± 9 ms/µg/ml, p=0.02), but there was no difference for Tpeak-Tend prolongation (39 ± 13 vs. 32 ± 13 ms/µg/ml, p=0.21). There was a delay (hysteresis) between peak concentration and both maximum QTc and Tpeak-Tend prolongation and a trend toward higher serum quinidine concentration in men than women. Analysis controlling for hysteresis showed no sex difference for QTc (55 ± 18 vs. 43 ± 19 ms/µg/ml, p=0.14), without changing the lack of sex difference with Tpeak-Tend (61 ± 22 vs. 55 ± 21 ms/µg/ml, p=0.49). CONCLUSIONS: Women do not have a greater quinidine-induced Tpeak-Tend prolongation than men. Sex differences in hysteresis and serum quinidine concentration in this study may have contributed to sex differences in quinidine-induced QTc prolongation.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Quinidina/efeitos adversos , Quinidina/sangue , Torsades de Pointes/sangue , Torsades de Pointes/induzido quimicamente , Adolescente , Adulto , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacocinética , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Masculino , Quinidina/administração & dosagem , Reprodutibilidade dos Testes , Medição de Risco/métodos , Sensibilidade e Especificidade , Fatores Sexuais , Método Simples-Cego , Torsades de Pointes/diagnóstico , Adulto Jovem
15.
Clin Cancer Res ; 20(15): 3902-7, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24824310

RESUMO

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aprovação de Drogas , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Clorambucila/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Prognóstico , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
17.
J Clin Pharmacol ; 2013 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24214102

RESUMO

Single tablet, once-daily HIV treatment regimens offer patient convenience, the potential for increased adherence, and fewer patient-related dosing errors[1] . Stribild® (manufactured and marketed by Gilead Sciences; referred to as "applicant" in this report), a 4-drug fixed-dose combination (FDC) tablet, is approved for the treatment of HIV-1 infection in treatment-naïve adult patients. Stribild® contains elvitegravir (an integrase strand transfer inhibitor), cobicistat (an inhibitor of cytochrome P450 enzymes), and the nucleoside/nucleotide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).

18.
Gastroenterology ; 144(7): 1450-1455.e2, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23470616

RESUMO

BACKGROUND & AIMS: Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development. METHODS: We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals. RESULTS: The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection. CONCLUSIONS: SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.


Assuntos
Antivirais/uso terapêutico , Determinação de Ponto Final/métodos , Hepatite C Crônica/tratamento farmacológico , Carga Viral , Adolescente , Adulto , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Antivirais/administração & dosagem , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/uso terapêutico , Masculino , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Prolina/administração & dosagem , Prolina/análogos & derivados , Prolina/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
20.
Clin Infect Dis ; 55(5): 639-44, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22652581

RESUMO

BACKGROUND: The purpose of this research was to compare interferon (IFN) responsiveness in treatment-naive and pegylated interferon α-ribavirin (P/R)-experienced subjects and to understand the implications of comparability in IFN responsiveness across treatment courses on drug development and clinical decision making. METHODS: Data from 3750 subjects treated with P/R in 8 trials were reviewed. The change in hepatitis C virus (HCV) RNA at week 4 in response to P/R was compared according to end-of-study (EOS) status (responder, relapser, partial and null responder) for treatment-naive subjects and the previous P/R response status (known as prior relapsers, prior partial responders, and prior null responders at the baseline) for P/R-experienced subjects. RESULTS: In subjects receiving a first course of P/R treatment (treatment-naive subjects), HCV RNA change after 4 weeks of P/R was correlated with EOS status on a P/R regimen. Importantly, for the first time, we have quantitatively demonstrated that IFN responsiveness in P/R-experienced subjects administered a second course of P/R treatment was similar to the IFN responsiveness in the treatment-naive subjects with corresponding EOS status. CONCLUSIONS: We contend that P/R-experienced subjects are represented within treatment-naive subjects. There are 2 important implications of this finding: (1) from a drug development perspective, a successful direct antiviral plus P/R therapy (IFN-based triple therapy) trial in P/R-experienced subjects may serve as supportive evidence in treatment-naive subjects; and (2) from a clinical decision perspective, previous P/R exposure should not alter new treatment decisions involving IFN-based triple therapy, as the IFN responsiveness to a second course of IFN is comparable.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Hepatite C/sangue , Hepatite C/virologia , Humanos , Razão de Chances , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Carga Viral
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