RESUMO
BACKGROUND: Following the introduction of rotavirus immunization in 2006 in the United States, there were substantial declines in the domestic rotavirus disease burden. In this study, we assess the value for money achieved by the program in the decade following vaccine introduction. METHODS: We applied an age-specific, static, multicohort compartmental model to examine the impact and cost-effectiveness of the US rotavirus immunization program in children <5 years of age using healthcare utilization data from 2001 to 2015 inclusive. We calculated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained from both a healthcare system and societal perspective. RESULTS: Declines in healthcare use associated with the rotavirus and acute gastroenteritis occurred from 2006 and continued to grow before stabilizing from 2010 through 2011. From 2011 to 2015, an estimated annual average of approximately 118 000 hospitalizations, 86 000 emergency department presentations, and 460 000 outpatient and physician office visits were prevented. From a societal perspective during this same period, the program was estimated to be cost saving in the base case model and in >90% of probabilistic sensitivity analysis simulations and from a healthcare system perspective >98% of simulations found an ICER below $100 000 per QALY gained. CONCLUSIONS: After the program stabilized, we found the rotavirus immunization in the United States was likely to have been cost saving to society. The greater than expected healthcare and productivity savings reflect the success of the rotavirus immunization program in the United States.
Assuntos
Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Criança , Pré-Escolar , Redução de Custos , Análise Custo-Benefício , Humanos , Programas de Imunização , Lactente , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Estados Unidos , VacinaçãoRESUMO
1. The absorption, distribution, metabolism and excretion of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 µCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95-99% of the dose from rats in 168 h post-dose and 82.4% from human volunteers in 504 h post-dose. In rat bile, approximately 35-42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with <12% of the dose excreted in rat urine and <10% of the dose excreted in human urine. 3. Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats.
Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Triazinas/farmacocinética , Aminopiridinas/sangue , Aminopiridinas/urina , Animais , Antineoplásicos/sangue , Antineoplásicos/urina , Bile/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Rim/metabolismo , Fígado/metabolismo , Redes e Vias Metabólicas , Ratos , Espectrometria de Massas em Tandem , Triazinas/sangue , Triazinas/urinaRESUMO
Variable numbers of tandem repeats (VNTR) typing is widely used for studying the bacterial cause of tuberculosis. Knowledge of the rate of mutation of VNTR loci facilitates the study of the evolution and epidemiology of Mycobacterium tuberculosis. Previous studies have applied population genetic models to estimate the mutation rate, leading to estimates varying widely from around 10â»5 to 10⻲ per locus per year. Resolving this issue using more detailed models and statistical methods would lead to improved inference in the molecular epidemiology of tuberculosis. Here, we use a model-based approach that incorporates two alternative forms of a stepwise mutation process for VNTR evolution within an epidemiological model of disease transmission. Using this model in a Bayesian framework we estimate the mutation rate of VNTR in M. tuberculosis from four published data sets of VNTR profiles from Albania, Iran, Morocco and Venezuela. In the first variant, the mutation rate increases linearly with respect to repeat numbers (linear model); in the second, the mutation rate is constant across repeat numbers (constant model). We find that under the constant model, the mean mutation rate per locus is 10⻲·°6 (95% CI: 10⻲·6¹,10⻹·58)and under the linear model, the mean mutation rate per locus per repeat unit is 10⻲·45 (95% CI: 10⻳·°7,10⻹·94). These new estimates represent a high rate of mutation at VNTR loci compared to previous estimates. To compare the two models we use posterior predictive checks to ascertain which of the two models is better able to reproduce the observed data. From this procedure we find that the linear model performs better than the constant model. The general framework we use allows the possibility of extending the analysis to more complex models in the future.
Assuntos
Evolução Molecular , Repetições Minissatélites , Modelos Genéticos , Mycobacterium tuberculosis/genética , Teorema de Bayes , Biologia Computacional , Simulação por Computador , DNA Bacteriano/genética , Bases de Dados de Ácidos Nucleicos , Humanos , Modelos Lineares , Mutação , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/etiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/transmissãoRESUMO
As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.
Assuntos
Neoplasias da Mama , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Idoso , Aminopiridinas , Digoxina , Interações Medicamentosas , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Membrana Transportadoras , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Preparações Farmacêuticas , Recidiva , Rosuvastatina Cálcica , TriazinasRESUMO
CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Adulto , Humanos , Voluntários Saudáveis , Meia-Vida , Relação Dose-Resposta a Droga , Método Duplo-CegoRESUMO
INTRODUCTION: The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of ~ 100 µg AG-221 containing approximately 300 nCi of [14C]-AG-221. METHODS: This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study. After an overnight fast of at least 10 h, the subjects received an oral dose (coated tablet) of 100 mg of AG-221 at 0 h on dosing day. Four hours after the oral dose, the subjects received 100 µg AG-221 containing ~ 300 nCi of [14C]-AG-221 administered as an IV bolus. Blood samples were collected and analyzed for plasma concentrations of AG-221 and [14C]-AG-221 using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) system and high-performance liquid chromatography (HPLC) fractionation followed by accelerator mass spectrometry analysis (AMS), respectively. Safety was evaluated throughout the study. RESULTS: The absolute BA after a 100-mg oral dose of AG-221 was measured as 57.2%. While the total clearance was 1.37 L/h, ~ 1/60 of the liver blood flow in a typical 70-kg human subject, the first-pass extraction was estimated to be less than 2%, assuming that the total clearance was entirely due to liver metabolism. Thus, the fraction of the AG-221 dose absorbed was at least 50%. AG-221 was safe and well tolerated when given under fasted conditions in a single 100-mg dose as a coated tablet with a microtracer [14C]-AG-221 solution, as few drug-related treatment-emergent adverse events (TEAEs) were reported. No clinically significant changes or findings were noted in the clinical laboratory evaluations, vital sign measurements, and electrocardiograms (ECGs) performed during this study. CONCLUSIONS: In healthy subjects under fasting conditions, the absolute BA following oral administration of a 100-mg AG-221 tablet was 57.2%. AG-221 was safe and well tolerated in healthy male subjects when administered as a single 100-mg film-coated tablet plus 100 µg [14C]-AG-221 given intravenously. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02443168. FUNDING: Celgene Corporation.
RESUMO
spolTools is a collection of online programs designed to manipulate and analyze spoligotype datasets of the Mycobacterium tuberculosis complex. These tools are integrated into a repository currently containing 1179 spoligotypes and 6278 isolates across 30 datasets. Users can search this database to export for external use or to pass on to the integrated tools. These tools include the computation of basic population genetic quantities, the visualization of clusters of spoligotype patterns based on an estimated evolutionary history and a procedure to predict emerging strains - genotypes associated with elevated transmission.
Assuntos
Biologia Computacional/métodos , Mycobacterium tuberculosis/classificação , Software , Tuberculose Pulmonar/epidemiologia , Animais , Humanos , Internet , Epidemiologia Molecular , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/microbiologiaRESUMO
Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on pomalidomide exposure. Following administration of a single oral dose of 4-mg pomalidomide, the geometric mean ratios of pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of pomalidomide plasma peak exposures (Cmax ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).
Assuntos
Fatores Imunológicos/farmacocinética , Hepatopatias/metabolismo , Fígado/metabolismo , Talidomida/análogos & derivados , Idoso , Área Sob a Curva , Voluntários Saudáveis , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/sangue , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Talidomida/efeitos adversos , Talidomida/sangue , Talidomida/farmacocinéticaRESUMO
BACKGROUND: Molecular typing methods are commonly used to study genetic relationships among bacterial isolates. Many of these methods have become standardized and produce portable data. A popular approach for analyzing such data is to construct graphs, including phylogenies. Inferences from graph representations of data assist in understanding the patterns of transmission of bacterial pathogens, and basing these graph constructs on biological models of evolution of the molecular marker helps make these inferences. Spoligotyping is a widely used method for genotyping isolates of Mycobacterium tuberculosis that exploits polymorphism in the direct repeat region. Our goal was to examine a range of models describing the evolution of spoligotypes in order to develop a visualization method to represent likely relationships among M. tuberculosis isolates. RESULTS: We found that inferred mutations of spoligotypes frequently involve the loss of a single or very few adjacent spacers. Using a second-order variant of Akaike's Information Criterion, we selected the Zipf model as the basis for resolving ambiguities in the ancestry of spoligotypes. We developed a method to construct graphs of spoligotypes (which we call spoligoforests). To demonstrate this method, we applied it to a tuberculosis data set from Cuba and compared the method to some existing methods. CONCLUSION: We propose a new approach in analyzing relationships of M. tuberculosis isolates using spoligotypes. The spoligoforest recovers a plausible history of transmission and mutation events based on the selected deletion model. The method may be suitable to study markers based on loci of similar structure from other bacteria. The groupings and relationships in the spoligoforest can be analyzed along with the clinical features of strains to provide an understanding of the evolution of spoligotypes.
Assuntos
Evolução Molecular , Transferência Genética Horizontal/genética , Modelos Genéticos , Mycobacterium tuberculosis/genética , Polimorfismo Genético , Genótipo , Sequências Repetitivas de Ácido Nucleico/genéticaRESUMO
OBJECTIVE: To assess whether pomalidomide can distribute into human semen and its duration in human semen. METHOD: A phase 1, randomized, double-blind, placebo-controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day -1 and 4 hours after dosing on Day 4 to quantify the pomalidomide concentrations in ejaculate after multiple oral doses of pomalidomide. RESULT: Our study showed that pomalidomide was present in male subjects' semen samples, and the average amount of pomalidomide in a single ejaculate 4 hours after dosing was less than 0.0022% of the daily 2 mg dose. There was a good correlation between the semen concentrations and the plasma concentrations, suggesting that the plasma concentration may be the main driving force for the distribution of pomalidomide into the seminal reservoirs. Simulation results suggest that pomalidomide was undetectable in semen 48 hours after stopping dosing. CONCLUSION: Based on the results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration includes a statement that "pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm."
RESUMO
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.
Assuntos
Fumar Cigarros , Citocromo P-450 CYP1A2/metabolismo , Interações Medicamentosas , Talidomida/análogos & derivados , Adulto , Idoso , Área Sob a Curva , Cafeína/administração & dosagem , Cafeína/farmacocinética , Cafeína/farmacologia , Indutores do Citocromo P-450 CYP1A2/administração & dosagem , Indutores do Citocromo P-450 CYP1A2/farmacocinética , Indutores do Citocromo P-450 CYP1A2/farmacologia , Inibidores do Citocromo P-450 CYP1A2/administração & dosagem , Inibidores do Citocromo P-450 CYP1A2/farmacocinética , Inibidores do Citocromo P-450 CYP1A2/farmacologia , Fluvoxamina/administração & dosagem , Fluvoxamina/farmacocinética , Fluvoxamina/farmacologia , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Talidomida/administração & dosagem , Talidomida/farmacocinéticaRESUMO
OBJECTIVE: The aim of this study was to evaluate the bioavailability of a pomalidomide oral liquid suspension relative to the commercial capsule formulation and to assess the food effect on the pomalidomide oral liquid suspension when administered as a single 4 mg dose. METHODS: This was an open-label, randomized, three-period, two-sequence crossover study in healthy subjects consisting of a screening phase, a baseline assessment phase, a treatment phase with three periods, and a follow-up phone call phase. Blood samples for pharmacokinetics (PK) assessment were collected up to 48 h postdose during each treatment period. Safety was evaluated throughout the study. RESULTS: Pomalidomide exposures were comparable in healthy subjects administered with a single oral 4 mg dose as the reference capsule or as the test liquid suspension formulations, demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve calculated from time 0 to the last measurable concentration at time t (AUC0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), and peak (maximum) plasma drug concentration (Cmax) were completely contained within the bioequivalence range of 80-125%. Administration of the pomalidomide liquid suspension with a high fat meal resulted in a 3.0 h delay in pomalidomide time to Cmax (tmax) and an ~ 34.5% reduction in Cmax. However, the AUCs were comparable after dose administration with and without food. CONCLUSION: A single oral dose of 4 mg of liquid suspension was bioequivalent to a single oral dose of 4 mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4 mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions.
RESUMO
OBJECTIVE: This study was conducted to characterize the pharmacokinetic and safety profile of rabeprazole sodium tablets in children and adolescents with gastroesophageal reflux disease (GERD). METHODS: This was a multicenter, open-label, single- and multiple-dose study in subjects aged 12 to 16 years with GERD. Subjects were stratified by age (12-<14 years and 14-16 years) and were randomized to receive oral rabeprazole 10 or 20 mg/d over 5 or 7 days (to accommodate weekends). The pharmacokinetic parameters calculated included C(max), T(max), AUC, t(1/2), and apparent oral clearance (day 5/7 only). Blood samples for pharmacokinetic determinations were obtained on study days 1, 2, and 5 (or 7) and at discharge on day 6 (or 8). Safety assessments, including adverse events (AEs), were performed at all study visits. RESULTS: Twenty-four subjects were enrolled in the study (12 in each dose group); they were predominantly white, had a mean age of 14.2 years, and had a mean body mass index of 24.3 kg/m(2) (the 90th percentile for adolescents of this age in the United States). Mean age and weight did not differ significantly between the 2 dose groups. On day 1, C(max) was significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.024); on day 5/7, both AUC and C(max) were significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.005 and P = 0.007, respectively). Within-period comparisons for both groups indicated that the AUC and C(max) for rabeprazole and its thioether metabolite did not differ significantly from day 1 to day 5/7. In addition, the T(max) and t(1/2) were relatively unchanged from day 1 to day 5/7 in both dose groups. Treatment-emergent signs and symptoms occurred in 11 subjects, 6 in the 10-mg group and 5 in the 20-mg group. The most frequently reported AEs were headache and nausea (16.7% and 8.3%, respectively). No statistically significant differences were observed between dose groups in terms of the number of subjects with AEs. CONCLUSIONS: Rabeprazole 10 and 20 mg were well tolerated in these children and adolescents with GERD. The results of the pharmacokinetic analyses of single and multiple oral doses indicated no apparent accumulation of rabeprazole or its thioether metabolite with the 10-mg dose. There was, however, a suggestion of accumulation with multiple dosing of rabeprazole 20 mg, which requires confirmation in larger studies.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis , Antiulcerosos , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons , 2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Adolescente , Análise de Variância , Antiulcerosos/administração & dosagem , Antiulcerosos/efeitos adversos , Antiulcerosos/farmacocinética , Área Sob a Curva , Criança , Esquema de Medicação , Feminino , Humanos , Masculino , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Rabeprazol , ComprimidosRESUMO
PURPOSE: Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated. METHODS: Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300-600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs. RESULTS: There were no significant changes in the maximum concentration (C max) and area under the plasma concentration-time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed. CONCLUSIONS: There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Talidomida/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adolescente , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Talidomida/administração & dosagem , Talidomida/farmacologia , Talidomida/uso terapêutico , Adulto JovemRESUMO
This study determines an optimal strategy for scaling up ART in Vietnam by examining three initiation thresholds [350 cells/mm(3), 500 cells/mm(3), and treat all people living with HIV (PLHIV) regardless of CD4 cell counts] and treatment commencement rates among treatment-eligible PLHIV ranging from 5% to 100% within 12 months of diagnosis. Incremental cost-effectiveness ratios (ICERs) were calculated using a Markov model, based on data from a cohort of 3449 patients who initiated ART between January 1, 2005 and December 31, 2009 in 13 outpatient clinics across six provinces in Vietnam. Our analyses indicated that raising treatment eligibility criteria, in line with WHO guidelines (CD4 ≤500 cells/mm(3)) or removing CD4-based criteria would both be cost-effective in Vietnam. However, the cost-effective strategy from an economic viewpoint is first to increase coverage substantially among those with lowest CD4 levels, and only when coverage increases towards saturation should initiation criteria be lifted. Universal coverage under current guidelines would cost an additional $85 million and $96 million per year if the treatment threshold was 500 cells/mm(3). These scenarios would avert 15,000 and 22,000 HIV-related deaths in 2010-2019, with ICERs of $500-$660 per QALY gained. It is imperative to increase treatment coverage for newly diagnosed PLHIV in Vietnam according to the current guidelines prior to increasing the CD4 threshold for ART initiation.
Assuntos
Fármacos Anti-HIV/economia , Terapia Antirretroviral de Alta Atividade/economia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Análise Custo-Benefício , Atenção à Saúde/economia , Feminino , Infecções por HIV/diagnóstico , Custos de Cuidados de Saúde , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Qualidade de Vida , Fatores Socioeconômicos , Resultado do Tratamento , Vietnã , Adulto JovemRESUMO
AIM: The objective of this study is are to examine the association of preadolescent obesity using body mass index (BMI) and waist circumference (WC) with health-related physical fitness components. METHODS: Grades 4 to 6 students in 2 private schools in Manila were included in this study. Height, weight, WC, and BMI were obtained. Physical fitness field tests were sit-and-reach test, 1-minute sit-ups, standing broad jump, 40-m sprint, and 20-m shuttle run. RESULTS: Obese subjects had poorer scores in the field tests except in the sit-and-reach test. BMI and WC were significantly negatively associated with all the physical fitness parameters, except for the 40-m sprint where positive correlation was observed, and in the sit-and-reach test where no correlation was seen. CONCLUSION: In the management of preadolescent overweight and obesity, exercise programs should therefore be designed toward enhancing these fitness parameters, while not sacrificing enjoyment and creativity.
Assuntos
Índice de Massa Corporal , Aptidão Física/fisiologia , Circunferência da Cintura/fisiologia , Criança , Feminino , Humanos , Masculino , Obesidade/epidemiologia , Obesidade/fisiopatologia , Filipinas/epidemiologiaRESUMO
PURPOSE: To investigate the pharmacokinetics and disposition of [(14)C]pomalidomide following a single oral dose to healthy male subjects. METHODS: Eight subjects were administered a single 2 mg oral suspension of [(14)C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro. RESULTS: Mean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean C(max), AUC(0-∞) and t(max) values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro. CONCLUSIONS: Following oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine.
Assuntos
Talidomida/análogos & derivados , Absorção , Administração Oral , Adulto , Radioisótopos de Carbono , Sistema Enzimático do Citocromo P-450/fisiologia , Humanos , Masculino , Fenótipo , Talidomida/administração & dosagem , Talidomida/farmacocinética , Adulto JovemRESUMO
The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration-QTc (C-QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C-QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C-QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.
Assuntos
Inibidores da Angiogênese/farmacologia , Talidomida/análogos & derivados , Adolescente , Adulto , Compostos Aza/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Eletrocardiografia , Fluoroquinolonas , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Quinolinas/farmacologia , Talidomida/farmacologia , Adulto JovemRESUMO
Homoplasy is the occurrence of genotypes that are identical by state but not by descent. It arises through a number of means including convergent and reverse evolution, and horizontal gene transfer. When using molecular markers that are based on sequences possessing a finite number of character states, such as VNTR or spoligotypes, this is an unavoidable phenomenon. Here we discuss the extent of homoplasy and its impact on inferences drawn from spoligotypes and VNTR in epidemiological studies of tuberculosis. To further explore this problem, we developed a computer simulation model combining the processes of mutation and transmission. Our results show that while the extent of homoplasy is not negligible, its effect on the proportion of isolates clustered ("n-1 method") is likely to be relatively low for spoligotyping. For VNTR-typing, homoplasy occurs at a low rate provided the number of loci used is high and the mutation rate is relatively high. However, deep phylogenetic inferences using spoligotypes or VNTRs with a small number of loci are likely to be unreliable.
Assuntos
DNA Bacteriano/química , Genótipo , Repetições Minissatélites , Mycobacterium tuberculosis/genética , Algoritmos , Simulação por Computador , Evolução Molecular , Humanos , Modelos Genéticos , Modelos Estatísticos , Taxa de Mutação , Mycobacterium tuberculosis/classificação , Tuberculose/epidemiologia , Tuberculose/transmissãoRESUMO
Variable numbers of tandem repeat (VNTR) loci and spoligotypes are molecular markers used to study genetic diversity of bacteria such as Mycobacterium tuberculosis. Knowledge about the rate at which molecular fingerprints change, or the mutation rate, is important for interpreting molecular epidemiological data and for studying quantitative models of the evolution and epidemiology of bacteria. In this paper we estimate the mutation rates of spoligotypes and VNTR loci of M. tuberculosis using published data sets from epidemiological studies. Our method makes use of a compound parameter: twice the product of the effective population size and the mutation rate. We use a standard procedure to estimate this population genetic parameter which describes genetic diversity. The ratio of estimated diversity parameters for different markers can be used to generate new estimates for markers with unknown mutation rates. We apply this method to generate new estimates along with confidence intervals. We found mutation rates for VNTR loci to be around 7x10(-4) to 1.5x10(-2) per locus per year, and for spoligotypes to be around 0.02-0.09 per year. The spoligotype rate is similar to previous estimates while the VNTR rates are at least an order of magnitude higher than previously reported. These findings confirm the high level of discrimination observed using multilocus VNTR typing, and suggest that caution should be taken not to underestimate the extent of recent transmission when using this marker.