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1.
Clin Pharmacol Drug Dev ; 11(8): 938-948, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35238179

RESUMO

Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1-single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2-multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half-life of ≈10 to 13 hours. The post absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple-dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5- to 2.5-fold higher than that observed in non-Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.


Assuntos
Acetatos , Quinazolinas , Acetatos/efeitos adversos , Acetatos/farmacocinética , Área Sob a Curva , Humanos , Taxa de Depuração Metabólica , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética
2.
Diabetol Int ; 13(1): 132-141, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35059249

RESUMO

AIMS: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. METHODS: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. RESULTS: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction (p < 0.05). The majority received biguanide (BG; 61%) or sulfonylurea (SU; 25%) add-on therapy. BG and SU groups showed a significant association between higher baseline HbA1c categories and greater HbA1c reductions (BG: - 0.24 to - 1.75%, p < 0.0001; SU: - 0.15 to - 2.11%, p < 0.0001). Lower HDL-cholesterol/higher non-HDL-cholesterol (BG), male gender (SU), and lower SBP (SU) were associated with larger HbA1c reductions. The results for baseline HbA1c (BG and SU) and gender (SU) were also confirmed by multivariate analysis. CONCLUSION: The majority of Japanese T2DM patients on sitagliptin monotherapy who require an add-on OAD utilized BG or SU. There were 2 determinants of glycemic response: baseline HbA1c with BG and SU and gender with SU during add-on OAD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00514-5.

3.
Pharm Stat ; 19(4): 436-453, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32072769

RESUMO

Many clinical research studies evaluate a time-to-event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ-year mean survival time is discussed as one of the alternative summary measures for the time-to-event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.


Assuntos
Análise de Sobrevida , Humanos , Neoplasias Pulmonares/mortalidade , Modelos de Riscos Proporcionais , Tamanho da Amostra , Fatores de Tempo , Resultado do Tratamento
4.
Hum Vaccin Immunother ; 16(9): 2292-2299, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045317

RESUMO

In July 2017, the Japanese Association for Infectious Diseases issued guidance for the administration of the PPSV23 revaccination. Despite increasing recognition of its protective benefits, levels of PPSV23 revaccination coverage rate in Japanese elderly population are unclear at present. Here, we report the results of a survey to know PPSV23 revaccination rates among elderly patients aged 65 and older. We asked an array of questions related to PPSV23 revaccination to Elderly adults and doctors across Japan via Web-based surveys in June 2018. The sampled population consisted of 5,085 men and women aged 65 and older. The PPSV23 revaccination coverage rate was estimated by survey questions regarded vaccination counts, intervals, and vaccine type. In addition, 400 internal medicine physicians were surveyed and asked about their reasons for recommending PPSV23 revaccination to elderly patients. In total, 1,648 elderly adults had received at least one PPSV23 dose; of these, 58 had received it at least twice (revaccination coverage rate: 3.5%). The most commonly cited justification for revaccination with PPSV23 among the surveyed physicians was that the benefits of revaccination exceed the risks of revaccination. In addition, multivariate analysis showed revaccinated status was most strongly associated with recommendations from peers (e.g. spouse, family, friends) among elderly subjects. This study reports PPSV23 revaccination coverage rate among Japanese adults aged 65 and older for the first time and concludes that the coverage rate is very low.


Assuntos
Médicos , Infecções Pneumocócicas , Adulto , Idoso , Feminino , Humanos , Imunização Secundária , Japão , Masculino , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas
5.
Hum Vaccin Immunother ; 16(7): 1521-1528, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31799889

RESUMO

The 23-valent capsular polysaccharide pneumococcal vaccine (PPSV23) was introduced in Japan's routine immunization schedule October 2014. It was recommended for adults aged 65 years (including those ≥65 during the transition period), and for adults 60-64 with cardiac, renal, or respiratory dysfunction equivalent to Level 1 physical disability. Several studies have shown that patients aged 50+ with chronic medical conditions (CMC) are at elevated risk of pneumococcal infection. Nonetheless, PPSV23 vaccination rates among this population remains low. In our study, we report the results of a survey investigation into PPSV23 vaccination rates among Japanese patients aged 50+ with CMC. Patients aged 50+ comprised the patient population (n = 5,078) and internal medicine physicians comprised the doctor population (n = 400) located all over Japan were asked an array of questions relevant to PPSV23 immunization in June 2018 via Web-based surveys. PPSV23 coverages among chronic patients aged 50-59, 60-64, and 65+ years were respectively 1.3%, 2.9%, and 37.8%. The high disease-specific PPSV23 rates seen in the 65+ group was 50.0% and 49.4%, for chronic liver disease and chronic lung disease, respectively. Doctors most frequently cited a lack of municipal subsidies as justification for recommending the vaccine to patients with CMC aged 50-64 years, and deference to patients' wishes as justification for patients with CMC aged 65+. In conclusion, PPSV23 has poor coverage among Japanese adults aged 50-64 with CMC. Doctors and local authorities need to raise public awareness to improve the vaccination rate, given the high risk of pneumococcal infectious disease among patients with CMC.


Assuntos
Infecções Pneumocócicas , Vacinas Pneumocócicas , Adulto , Idoso , Humanos , Japão , Pessoa de Meia-Idade , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Streptococcus pneumoniae
6.
Jpn J Infect Dis ; 72(5): 299-305, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31155600

RESUMO

Human papillomavirus (HPV)-associated disease is common among men with HPV infection. A quadrivalent HPV (qHPV) vaccine has demonstrated 85.9% efficacy against HPV6/11/16/18-related, persistent (≥ 6 month) infection in a study of Japanese men aged 16-26 years old. Here, we report the results of an open-label study of the immunogenicity and tolerability of the qHPV vaccine (NCT02576054), conducted to bridge findings from Japanese men to Japanese boys aged 9-15 years old. A total of 100 boys completed a three-vaccination regimen (Day 1, and Months 2 and 6), and 99 boys were included in the primary analysis population. The rate of seroconversion at one month after vaccine Dose 3 (Month 7) was high for each type of HPV (anti-HPV6/11/16/18 seroconversion rates [95% CI]: 94.9% [85.5%, 98.3%], 99.0% [94.4%, 100.0%], 99.0% [94.5%, 100.0%], and 99.0% [94.4%, 100.0%], respectively). Moreover, anti-HPV6/11/16/18 geometric mean titers were 482.9 mMU/mL, 1052.8 mMU/mL, 3878.3 mMU/mL, and 1114.5 mMU/mL, respectively. Immune responses to the qHPV vaccine were non-inferior among Japanese boys included in the current study and compared with young Japanese men from a separate study. Injection-site reactions were the most common adverse events, and administration of the vaccine was well tolerated in Japanese boys.


Assuntos
Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/efeitos adversos , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Infecções por Papillomavirus/prevenção & controle , Adolescente , Anticorpos Antivirais/sangue , Povo Asiático , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/administração & dosagem , Humanos , Masculino , Soroconversão
7.
J Infect Chemother ; 25(7): 520-525, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30879979

RESUMO

This study for the first time assessed quadrivalent human papillomavirus (qHPV) vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease in Japanese women (16-26 years old), as previously demonstrated in overseas trials, and vaccine safety in a longer term (48-month) open-label study (NCT01544478). Participants received three doses of qHPV vaccine (Day 1, Month 2, Month 6). Effectiveness endpoints, assessed in the per-protocol population, included incidence of HPV6/11/16/18-related cervical intraepithelial neoplasia (CIN) Grade 2 or worse (CIN Grade 2 and 3, adenocarcinoma in situ, and/or cervical cancer) as primary endpoint and incidence of external genital lesions (EGLs). Disease related to other high-risk HPV types was also assessed. Adverse events (AEs) and serious AEs (SAEs) were collected from Days 1-15 after any vaccination; vaccine-related SAEs, deaths, and new medical conditions were collected throughout the study. A total of 1030 women received at least one vaccination. No cases of CIN2 or worse or EGLs were reported in the per-protocol population. Injection site-related AEs were reported in 14.5% of participants; most were mild and resolved within 15 days. Vaccine-related systemic AEs occurred in 8.6% of participants, most commonly headache (2.3%), malaise (1.7%), and pyrexia (1.3%). There were no vaccine-related SAEs; one participant discontinued due to a vaccine-related AE of mild uticaria. Overall, qHPV vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease and EGLs was indicated in Japanese women. The vaccine was well-tolerated, without new safety signals throughout the 48-month study period. Findings are consistent with overseas qHPV vaccine pivotal trials. CLINICAL TRIAL REGISTRY: clinicaltrials.gov; NCT01544478.


Assuntos
Infecções por Papillomavirus/epidemiologia , Vacinas contra Papillomavirus/administração & dosagem , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Vacinação/métodos , Adolescente , Adulto , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Esquemas de Imunização , Incidência , Japão/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/efeitos adversos , Fatores de Tempo , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Vacinação/efeitos adversos , Adulto Jovem , Displasia do Colo do Útero/prevenção & controle , Displasia do Colo do Útero/virologia
8.
Vaccine ; 37(12): 1651-1658, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30797638

RESUMO

BACKGROUND: The quadrivalent (q) human papillomavirus (HPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, and 18. We report efficacy, immunogenicity, and safety of qHPV vaccine in a Phase 3 study in Japanese men. METHODS: In this randomized, double-blind trial (NCT01862874), Japanese men (aged 16-26 years) were randomized in a 1:1 ratio to receive three doses of qHPV vaccine or placebo (Day 1, Month 2, Month 6). The primary efficacy endpoint was the combined incidence of HPV6/11/16/18-related persistent anogenital infection (detected at ≥2 consecutive visits ≥6 months apart), assessed in the per-protocol population of men who received all three vaccinations, and were seronegative at Day 1 and PCR negative from Day 1 to Month 7 to the relevant HPV type. Results are from the interim and final analyses. RESULTS: In total, 1124 participants were randomized. The vaccine demonstrated 83.3% (95% confidence interval: 24.9, 98.2; p = 0.007) and 85.9% (95% confidence interval: 52.7, 97.3; p < 0.001) efficacy against HPV6/11/16/18-related persistent infection in the interim and final analyses, respectively. Two cases of HPV6/11/16/18-related external genital lesions (condyloma and PIN 1) were observed in the placebo group and none in the qHPV vaccine group at study end. At Month 7, >97% of participants who received qHPV vaccine seroconverted to each of the vaccine HPV types. Most participants remained seropositive at Month 36, although the seropositivity rate declined between Months 7 and 36. Vaccination-related adverse events were reported in 60.8% and 56.5% of participants in the qHPV vaccine and placebo groups, respectively; most commonly mild to moderate injection-site pain, erythema, and swelling. Injection-site pain and swelling were more common with qHPV vaccine than placebo (each p < 0.05). CONCLUSIONS: Results suggest qHPV vaccine is efficacious against HPV6/11/16/18-related persistent infections, immunogenic, and well-tolerated in Japanese men. Clinical trial registration identifier: NCT01862874.


Assuntos
Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Imunogenicidade da Vacina , Infecções por Papillomavirus/prevenção & controle , Adolescente , Adulto , Homossexualidade Masculina , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/administração & dosagem , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/efeitos adversos , Humanos , Japão/epidemiologia , Masculino , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/transmissão , Avaliação de Resultados da Assistência ao Paciente , Fatores de Risco , Fatores Sexuais , Vacinação/métodos , Adulto Jovem
9.
Diabetes Obes Metab ; 20(9): 2274-2281, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29770541

RESUMO

AIMS: To compare the effect of a dipeptidyl peptidase-4 inhibitor (DPP4-i) and a sulfonylurea (SU) on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 53 drug-naïve Japanese patients with T2DM (HbA1c, 7.0%-9.0%; fasting plasma glucose, 6.1 mmol/L or higher) were randomly assigned to either sitagliptin 50 mg qd or glibenclamide 2.5 mg per day (given in divided doses) in a 1:1 ratio. A continuous glucose monitoring (CGM) device was used to obtain 24-hour glucose profiles for each patient at baseline and at Week 2. The primary study endpoint was change from baseline in mean amplitude of glucose excursion (MAGE) during a 24-hour period. A key secondary endpoint was change from baseline in the standard deviation (SD) of 24-hour glucose levels. RESULTS: After 2 weeks of treatment, a numerically greater reduction in MAGE from baseline was observed in the sitagliptin group compared with the glibenclamide group, but the between-treatment difference was not statistically significant (LS mean difference [95% CI]: -0.48 mmol/L [-1.31, 0.34]; P = .245). However, a significantly greater reduction in the change from baseline in SD was observed in the sitagliptin group compared with the glibenclamide group (LS mean difference [95% CI]: -0.33 mmol/L [-0.62, -0.03]; P = .029). CONCLUSIONS: This study suggests that the DPP4 inhibitor sitagliptin has a greater ability to reduce daily glucose fluctuation than the SU glibenclamide in drug-naïve Japanese patients with T2DM. ClinicalTrials.gov: NCT02318693.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/administração & dosagem , Hipoglicemiantes/administração & dosagem , Fosfato de Sitagliptina/administração & dosagem , Idoso , Automonitorização da Glicemia , Diabetes Mellitus Tipo 2/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Esquema de Medicação , Jejum/sangue , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Compostos de Sulfonilureia/administração & dosagem , Resultado do Tratamento
10.
Jpn J Infect Dis ; 70(4): 368-373, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28003597

RESUMO

A 9-valent human papillomavirus (HPV 6/11/16/18/31/33/45/52/58) virus-like particle vaccine (9vHPV) has been proven highly efficacious in preventing anogenital diseases related to HPV, in a pivotal phase III study for women aged 16-26 years. Here, we report the results of an open-label phase III study conducted to bridge the gap between the findings in women aged 16-26 years and Japanese girls aged 9-15 years. All subjects (n = 100) received a 3-dose regimen of 9vHPV vaccine on day 1 and at months 2 and 6. Anti-HPV serological assays were performed on day 1 and at months 7, 12, 24, and 30. At month 7 (4 weeks after the third dose), 100% of the subjects exhibited seroconversion for each type of HPV. Increases in geometric mean of the titers for anti-HPV 6/11/16/18/31/33/45/52/58 in the subjects were similar to those in Japanese women aged 16-26 years in a previous phase III study. Persistence of the anti-HPV response was observed for 2 years after administration of the third dose. In addition, administration of the 9vHPV vaccine was generally well-tolerated in Japanese girls.


Assuntos
Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Vacinas de Partículas Semelhantes a Vírus/efeitos adversos , Vacinas de Partículas Semelhantes a Vírus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Formação de Anticorpos , Povo Asiático , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Esquemas de Imunização , Vacinas contra Papillomavirus/administração & dosagem , Fatores de Tempo , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Adulto Jovem
11.
J Diabetes Investig ; 8(1): 84-92, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27182005

RESUMO

AIMS/INTRODUCTION: Omarigliptin is a novel, potent, long-acting oral dipeptidyl peptidase-4 inhibitor being developed as a once-weekly (q.w.) treatment for type 2 diabetes mellitus patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan. MATERIALS AND METHODS: This was a two-part, double-blind, randomized, placebo-controlled study in healthy Japanese men to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of omarigliptin after single dose (5-100 mg) and multiple dose (1-50 mg q.w. for 3 weeks) administration. RESULTS: Omarigliptin was rapidly absorbed with a time to maximum concentration of 0.5-4 h. The pharmacokinetic profile was biphasic with a long terminal half-life >100 h. The area under the concentration-time curve from 0 to 168 h, maximum concentration and the concentration at 168 h post-dose increased dose-dependently after 3 weeks of once-weekly dosing for doses ranging 1-50 mg, with accumulation ratios ranging 1.03-1.35 and 0.87-1.36 for the area under the concentration-time curve from 0 to 168 h and maximum concentration, respectively. Plasma dipeptidyl peptidase-4 inhibition levels 1 week post-dose increased with dose, ranging 79.2-94.0% after 5-100 mg single dose administration and 51.3-90.2% after 1-50 mg multiple once-weekly dose administration. Administration with food did not meaningfully alter the pharmacokinetics of omarigliptin. Omarigliptin was generally well tolerated, with no hypoglycemia being reported. CONCLUSION: The results of the present study in healthy Japanese men showed that omarigliptin was well tolerated and had a pharmacokinetic and dipeptidyl peptidase-4 inhibition profile that supports once-weekly dosing in Japanese patients with type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Piranos/administração & dosagem , Piranos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Japão , Masculino , Piranos/efeitos adversos
12.
Ther Innov Regul Sci ; 50(6): 846-852, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30231736

RESUMO

BACKGROUND: This study provides the results of a survey on the current practice of multiplicity adjustment and sample size calculation in multi-arm clinical trials. METHODS: The survey was aimed at members of the Japan Pharmaceutical Manufacturers Association (JPMA) and was conducted in 2015. RESULTS: Of the 66 JPMA member companies, effective responses were obtained on 151 trials from 33 companies based in Japan and 11 companies based in other countries. The results from this survey indicate that multiplicity adjustment in confirmatory multi-arm trials is adequate in terms of controlling the familywise error rate. Multiplicity was adjusted in 38.3% of exploratory multi-arm trials. Various multiple comparison procedures (MCPs) were applied, with the fixed sequence procedure being the one applied most frequently. This survey also reveals that there are issues that need to be addressed within sample size calculation. CONCLUSIONS: To adequately design a multi-arm clinical trial, it is important within sample size calculation to consider whether to perform multiplicity adjustment, select MCPs, and define their power.

13.
J Infect Chemother ; 21(3): 170-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25572140

RESUMO

UNLABELLED: This was a phase I double-blind, randomized, placebo-controlled, 2-period, single-dose, crossover study in healthy Japanese subjects to evaluate the safety, tolerability, and pharmacokinetics of a single bolus injection of daptomycin. Twenty healthy subjects were randomized; 16 received a single intravenous (IV) administration of 6 mg/kg of daptomycin and 4 received a single intravenous administration of placebo (0.9% sodium chloride) by either bolus injection (10 s) or infusion (30 min) following an overnight fast in Periods 1 or 2. There was a minimum 5-day washout period from the administration in Period 1 to the administration in Period 2. Administration of a single bolus injection of daptomycin 6 mg/kg was generally well tolerated. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC0-∞, AUC0-24 h, Cmax, and C24 h of daptomycin in plasma following bolus injection over 10 s relative to IV infusion over 30 min were 1.01 (1.00, 1.03), 1.02 (1.00, 1.03), 1.50 (1.41, 1.60) and 1.05 (1.02, 1.08), respectively. Because no existing studies of this nature were available, Cmax following daptomycin 6 mg/kg/10 s multiple-dose bolus injections was simulated. It was estimated at 178 µg/mL (upper limit) and was expected to be equal to or less than the confirmed Cmax in Japanese or non-Japanese healthy subjects following single- or multiple-dose IV infusion over 30 min. From the results of this study, daptomycin multiple-dose bolus injections over 10 s are expected well tolerated and to have similar Cmax values as IV infusion over 30 min, thus offering potential clinical benefit. TRIAL REGISTRATION: Because this was a phase I trial in healthy subjects, the trial was not registered.


Assuntos
Antibacterianos/farmacocinética , Daptomicina/farmacocinética , Administração Intravenosa , Adulto , Antibacterianos/efeitos adversos , Disponibilidade Biológica , Estudos Cross-Over , Daptomicina/efeitos adversos , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Japão , Masculino , Distribuição Tecidual , Adulto Jovem
14.
PLoS One ; 9(5): e96919, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24810427

RESUMO

PURPOSE: To assess the association between statins and diverse adverse events in Japanese population. METHODS: New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009. RESULTS: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009). CONCLUSIONS: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Criança , Estudos de Coortes , Creatinina/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/enzimologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/urina , Feminino , Hematúria/induzido quimicamente , Hospitais/estatística & dados numéricos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteinúria/induzido quimicamente , Rabdomiólise/induzido quimicamente , Adulto Jovem
16.
Stat Med ; 26(3): 498-511, 2007 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-16596575

RESUMO

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test-drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut-off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut-off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut-off value to reduce the expected loss for various response patterns is 0.75 for a 3-group trial and 0.70 for a 4-group trial. Using these cut-off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable.


Assuntos
Ensaios Clínicos Fase II como Assunto/métodos , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Modelos Estatísticos , Asma/tratamento farmacológico , Humanos , Antagonistas de Leucotrienos/administração & dosagem , Pico do Fluxo Expiratório/efeitos dos fármacos
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