Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 189
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Clin Transl Sci ; 13(2): 352-361, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32053288

RESUMO

Generic entry of newer anticoagulants is expected to decrease the costs of atrial fibrillation management. However, when making switches between brand and generic medications, bioequivalence concerns are possible. The objectives of this study were to predict and compare the lifetime cost-effectiveness of brand dabigatran with hypothetical future generics. Markov microsimulations were modified to predict the lifetime costs and quality-adjusted life years of patients on either brand or generic dabigatran from a US private payer perspective. Event rates for generics were predicted using previously developed pharmacokinetic-pharmacodynamic models. The analyses showed that generic dabigatran with lower-than-brand systemic exposure were dominant. Meanwhile, generic dabigatran with extremely high systemic exposure was not cost-effective compared with the brand reference. Cost-effectiveness of generic medications cannot always be assumed as shown in this example. Combined use of pharmacometric and pharmacoeconomic models can assist in decision making between brand and generic pharmacotherapies.

3.
Perit Dial Int ; : 896860819889774, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065053

RESUMO

Intraperitoneal vancomycin is the first-line therapy in the management of peritoneal dialysis (PD)-related peritonitis. However, due to the paucity of data, vancomycin dosing for peritonitis in patients on automated peritoneal dialysis (APD) is empiric and based on clinical experience rather than evidence. Studies in continuous ambulatory peritoneal dialysis (CAPD) patients have been used to provide guidelines for dosing and are often extrapolated for APD use, but it is unclear whether this is appropriate. This review summarizes the available pharmacokinetic data used to inform optimal dosing in patients on CAPD or APD. The determinants of vancomycin disposition and pharmacodynamic effects are critically summarized, knowledge gaps explored, and a vancomycin dosing algorithm in PD patients is proposed.

4.
CPT Pharmacometrics Syst Pharmacol ; 9(3): 129-142, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31905263

RESUMO

Artificial intelligence, in particular machine learning (ML), has emerged as a key promising pillar to overcome the high failure rate in drug development. Here, we present a primer on the ML algorithms most commonly used in drug discovery and development. We also list possible data sources, describe good practices for ML model development and validation, and share a reproducible example. A companion article will summarize applications of ML in drug discovery, drug development, and postapproval phase.

6.
J Clin Pharmacol ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31802503

RESUMO

Acetaminophen protein adducts (adducts) are a well-established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent-metabolite modeling. It demonstrated formation-limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long elimination half-life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles with those observed in an independent cohort of children. The scaled model significantly overpredicted the adduct concentrations in children early on in treatment and underpredicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely because of increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semimechanistic understanding of varying profiles of adduct exposure in adults and children.

7.
J Clin Pharmacol ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31879975

RESUMO

Uridine diphosphate glucuronosyltransferases (UGTs) catalyze glucuronidation to facilitate systemic and local clearance of numerous chemicals and drugs. To investigate whether UGT expression is coregulated in human liver, we analyzed the protein expression of UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 using western blots from 164 healthy human liver samples, comparing expression with age and sex. UGT1A6 levels were significantly higher in children than adults, and UGT3A1 and 3A2 expression significantly increased with age from childhood to age >65 yearas. In children aged <18 years, UGT1A4/1A9 protein expression was significantly correlated, but not for adults aged >18 years. UGT1A3 expression was always significantly correlated with other UGT1A isoforms in all adults aged >18 years. In individuals aged ≥12 years, expression of UGT1A1/1A4, UGT1A1/1A6, UGT1A1/1A9, and UGT1A4/1A6 significantly correlated, which was not observed in children aged <12 years. In contrast, UGT1A4/2B7 showed significant correlation in children aged <12 years, but not in individuals aged ≥12 years, and this was observed in female but not male individuals. Expression of UGT1A6/1A9 and UGT3A1/3A2 correlated in the entire sample population, but UGT3As did not correlate with other UGTs. These correlations were sex dependent, as UGT1A3/1A1, UGT1A4/2B7 and UGT3A1/3A2 correlated more highly in male than female individuals, while UGT1A4/1A6 protein correlated more significantly in female than male individuals. This is the first report on the ontogeny of UGT3A isoforms, showing maximal expression in the elderly, and is the first demonstration that UGT isoforms commonly coexpress in vivo, in both age-dependent and sex-dependent manners.

8.
Mult Scler Relat Disord ; 39: 101893, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31865273

RESUMO

BACKGROUND: The risk of progressive multifocal leukoencephalopathy limits the duration over which patients can receive natalizumab before requiring a switch to other therapies such as fingolimod. To date, no studies have assessed the long-term real-world effectiveness and safety of fingolimod following a switch from natalizumab. We aimed to investigate the benefit-risk profile of fingolimod over 48 months in patients switching from natalizumab, and the impact of washout duration after natalizumab discontinuation on outcomes during fingolimod treatment. METHODS: This analysis used data from PANGAEA, an ongoing German multicenter, prospective, non-interventional, observational study. In total, 3912 patients were included: 530 had switched from natalizumab (natalizumab subpopulation), and a reference population of 3382 had switched from other treatments or were treatment-naïve (non-natalizumab subpopulation). The natalizumab subpopulation was stratified by washout duration (30-89 days, 90-149 days, and ≥ 150 days) prior to fingolimod initiation. RESULTS: In the natalizumab subpopulation over 48 months of fingolimod treatment, 58.2% (n = 227/390) of patients remained on fingolimod. Over this period, mean annualized relapse rates (ARRs) and proportions of patients who relapsed were similar across washout durations, and ranged from 0.455 (95% confidence interval [CI]: 0.363-0.571) to 0.546 (95% CI: 0.446-0.669) and 54.1% (n = 92/170) to 60.2% (n = 127/211), respectively. Overall, 17.1% (n = 36/211) had 6-month confirmed disability worsening. In the non-natalizumab subpopulation, ARR was 0.300, 40.9% (n = 1325/3237) of patients relapsed, and a similar proportion to the natalizumab subpopulation had 6-month disability worsening (16.6% [n = 232/1394]). In both subpopulations, the safety profile of fingolimod was consistent with that observed in randomized controlled trials. CONCLUSIONS: In patients discontinuing natalizumab, fingolimod has a favorable benefit-risk profile over 48 months. These findings also suggest using a short washout following natalizumab discontinuation, consistent with guidelines and current clinical practice in Germany.

9.
Theranostics ; 9(25): 7525-7536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695784

RESUMO

Aberrant innate immune response drives the pathophysiology of many diseases. Myeloperoxidase (MPO) is a highly oxidative enzyme secreted by activated myeloid pro-inflammatory immune cells such as neutrophils and macrophages, and is a key mediator of the damaging innate immune response. Current technologies for detecting MPO activity in living organisms are sparse and suffer from any combination of low specificity, low tissue penetration, or low spatial resolution. We describe a versatile imaging platform to detect MPO activity using an activatable construct conjugated to a biotin moiety (MPO-activatable biotinylated sensor, MABS) that allows monitoring the innate immune response and its modulation at different scales and settings. Methods: We designed and synthesized MABS that contains MPO-specific and biotin moieties, and validated its specificity and sensitivity combining with streptavidin-labeled fluorescent agent and gold nanoparticles imaging in vitro and in vivo in multiple mouse models of inflammation and infection, including Matrigel implant, dermatitis, cellulitis, cerebritis and complete Fraud's adjuvant (CFA)-induced inflammation. Results: MABS MPO imaging non-invasively detected varying MPO concentrations, MPO inhibition, and MPO deficiency in vivo with high sensitivity and specificity. MABS can be used to obtain not only a fluorescence imaging agent, but also a CT imaging agent, conferring molecular activity information to a structural imaging modality. Importantly, using this method on tissue-sections, we found that MPO enzymatic activity does not always co-localize with MPO protein detected with conventional techniques (e.g., immunohistochemistry), underscoring the importance of monitoring enzymatic activity. Conclusion: By choosing from different available secondary probes, MABS can be used to create systems suitable to investigate and image MPO activity at different scales and settings.

15.
J Clin Pharmacol ; 59 Suppl 1: S42-S55, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502688

RESUMO

An understanding of the postnatal development of hepatic UDP-glucuronosyltransferase (UGT) enzymes is required for accurate prediction of the age-dependent changes in pharmacokinetics of many drugs used in children. However, the maturation rate of hepatic UGT isoforms remains a major knowledge gap. This study aimed to establish the age-associated changes in glucuronidation activity of 10 major hepatic UGT isoforms in humans, namely, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15, and UGT2B17. Human liver microsomes from pediatric and adult donors were incubated under optimized incubation conditions to assess the activity rates of hepatic UGT isoforms using a panel of 19 in vitro UGT probe substrates and clinically used drugs. Statistically strong correlations of glucuronidation activities allowed the ontogeny of UGT1A1, UGT1A4, UGT2B7, UGT2B10, and UGT2B15 to be established using multiple selective UGT substrates and matched human liver microsome samples. The postnatal development of hepatic UGTs is isoform-dependent using either individual or cross-correlated selective isoform substrates. Maximal adult activity was reached at different times ranging from within a month (UGT1A1, UGT2B4, UGT2B7, UGT2B10, and UGT2B15), during infancy (UGT1A3, UGT1A4, and UGT1A9), to adolescence (UGT1A6 and UGT2B17). This study provides an extensive characterization of the postnatal ontogeny profiles of hepatic UGT enzymes that are instrumental for predicting drug disposition via in vitro-in vivo extrapolation algorithms and verifying pharmacokinetic predictions against in vivo observations via pediatric physiologically based pharmacokinetic modeling in pediatric patients.

16.
J Pharm Sci ; 108(12): 3842-3847, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539541

RESUMO

In the present study, an in vitro-in vivo extrapolation of dissolution integrated to a physiologically based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a self-buffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product development, manufacturing changes and setting clinically relevant specifications for immediate release formulations containing ibuprofen and other weak acids with similar properties.

18.
Mult Scler Relat Disord ; 35: 262-269, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437741

RESUMO

BACKGROUND: Quality of life (QoL) is significantly impaired in patients with Multiple Sclerosis (MS). As the expanded disability status scale (EDSS) inadequately reflects the impact of clinical symptoms on QoL, the present study aimed to identify factors associated with reduced QoL in MS patients. DESIGN: Single-center cross-sectional study in 260 MS patients. METHODS: QoL was assessed by the Multiple Sclerosis International QoL Questionnaire (MusiQoL), depression by the Center for Epidemiological Studies Depression Scale (CES-D scale), and fatigue by the Fatigue Scale for motor function and cognition (FSMC). RESULTS: 79.6% patients were female and 21.4% male. The mean age was 44.5 ±â€¯11.2 years and the median EDSS 3.0 (range 0.0-8.5). 35.8% had depression and 56.9% moderate to severe fatigue. The mean MusiQoL index score was 73.9 ±â€¯11.3. Using linear regression, depression, fatigue, family status, physical activity, and occupation were associated with QoL. EDSS was only associated with QoL in patients with an EDSS 0.5.0. CONCLUSIONS: Depression, fatigue, family status, physical activity, and occupational status were closely associated with QoL in MS patients. Potential measures to improve QoL include assessment and treatment of depression, physical exercise, and maintaining patients employed in accordance with their physical and mental disabilities.

19.
Ther Adv Cardiovasc Dis ; 13: 1753944719863641, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364490

RESUMO

BACKGROUND: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide. METHODS: A post hoc exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes. RESULTS: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax) in the 5th and 95th percentiles versus the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with Cmax [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no versus yes)]. CONCLUSIONS: The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Modelos Biológicos , Rivaroxabana/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Isquemia Encefálica/mortalidade , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Acidente Vascular Cerebral/mortalidade , Resultado do Tratamento
20.
Int J Gynaecol Obstet ; 147(3): 397-403, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31402446

RESUMO

OBJECTIVE: To describe obstetrical care and in-hospital outcomes in very preterm triplet pregnancies in a European multiregional cohort. METHODS: Data from a prospective population-based study of very preterm births between 22 + 0 and 31 + 6 weeks of gestation in 19 regions from 11 European countries participating in the EPICE project in 2011/2012 were used to describe triplet pregnancies and compare them with twins and singletons. RESULTS: Triplets constituted 1.1% of very preterm pregnancies (97/8851) and 3.3% of very preterm live births (258/7900); these percentages varied from 0% to 2.6% and 0% to 6% respectively across the regions. In-hospital mortality after live birth was 12.4% and did not differ significantly from singletons or twins or by birth order. However, 28.9% of mothers with a triplet pregnancy experienced at least one neonatal death. Ninety percent of live-born triplets were delivered by cesarean. Vaginal delivery was associated with an Apgar score of less than 7, but not with in-hospital mortality. CONCLUSIONS: The prevalence of very preterm triplets varies across European regions. Most triplets were born by cesarean and those born vaginally had lower Apgar scores. Overall, in-hospital mortality after live birth was similar to singletons and twins.


Assuntos
Gravidez de Trigêmeos/estatística & dados numéricos , Nascimento Prematuro/epidemiologia , Trigêmeos/estatística & dados numéricos , Adulto , Peso ao Nascer , Estudos de Casos e Controles , Cesárea/estatística & dados numéricos , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Nascimento Vivo/epidemiologia , Gravidez , Estudos Prospectivos , Natimorto/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA