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1.
Respirology ; 28(9): 851-859, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37364930

RESUMO

BACKGROUND AND OBJECTIVE: Weight and muscle loss are predictors of poor outcomes in chronic obstructive pulmonary disease. However, to our knowledge, no study has investigated the predictors of longitudinal weight loss or its composition from functional and morphological perspectives. METHODS: This longitudinal observational study with a median follow-up period of 5 years (range: 3.0-5.8 years) included patients with COPD and ever-smokers at risk of COPD. Using chest computed tomography (CT) images, airway and emphysematous lesions were assessed as the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) and the percentage of low attenuation volume (LAV%). Muscle mass was estimated using cross-sectional areas (CSAs) of the pectoralis and erector spinae muscles, and fat mass was estimated using the subcutaneous fat thickness at the level of the 8th rib measured using chest CT images. Statistical analyses were performed using the linear mixed-effects models. RESULTS: In total, 114 patients were enrolled. Their body mass index remained stable during the study period while body weight and muscle CSA decreased over time and the subcutaneous fat thickness increased. Reduced forced expiratory volume in 1 s and peak expiratory flow (PEF) at baseline predicted the future decline in muscle CSA. CONCLUSION: Severe airflow limitation predicted future muscle wasting in patients with COPD and ever-smokers at risk of COPD. Airflow limitation with a PEF slightly below 90% of the predicted value may require intervention to prevent future muscle loss.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Fumantes , Humanos , Fumar/efeitos adversos , Fumar/epidemiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Pulmão , Volume Expiratório Forçado , Músculos/patologia , Peso Corporal
2.
Antimicrob Agents Chemother ; 66(10): e0063222, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36094202

RESUMO

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Indazóis , Triazinas , Adulto , Humanos , Administração Oral , Antivirais/farmacocinética , Antivirais/uso terapêutico , Área Sob a Curva , Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores Enzimáticos , Voluntários Saudáveis , Midazolam/uso terapêutico , Peptídeo Hidrolases , Inibidores de Proteases , SARS-CoV-2 , Indazóis/farmacocinética , Indazóis/uso terapêutico , Triazinas/farmacocinética , Triazinas/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico
3.
Antimicrob Agents Chemother ; 59(11): 6755-62, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26282420

RESUMO

UNLABELLED: Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. SUBJECTS: Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.


Assuntos
Ciclopentanos/sangue , Ciclopentanos/farmacocinética , Guanidinas/sangue , Guanidinas/farmacocinética , Influenza Humana/sangue , Ácidos Carbocíclicos , Voluntários Saudáveis , Humanos , Japão , Modelos Teóricos , Método de Monte Carlo , Estados Unidos
4.
J Infect Chemother ; 21(2): 123-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25487084

RESUMO

Integrated analysis of all plasma concentration data obtained from phase 1 studies in Japanese subjects, including a high dose study and special population studies, was conducted to thoroughly re-investigate the pharmacokinetics of doripenem by means of a population approach. Dose adjustments for patients with renal impairment were assessed by Monte-Carlo pharmacokinetics/pharmacodynamics simulation. The population pharmacokinetics of doripenem was evaluated using 921 plasma concentration data from 92 subjects from eight phase 1 studies in Japan. The two-compartment model could well describe the plasma concentration profile of doripenem after intravenous infusion. Creatinine clearance and age were found to be covariates of doripenem clearance, and creatinine clearance was the most important factor influencing the pharmacokinetics of doripenem, which is consistent with the fact that doripenem is mainly excreted via the urine. Simulations suggest that exposures (AUC) to 1 g every 8 h for patients with normal renal function would be similar to those expected at 1 g every 12 h, 0.5 g every 8 h and 0.25 g every 8 h for patients with mild, moderate and severe renal impairment, respectively. These dosing regimens also provide sufficient exposure to doripenem from the viewpoint of the percentage of time above the minimum inhibitory concentration.


Assuntos
Antibacterianos/farmacocinética , Carbapenêmicos/farmacocinética , Modelos Biológicos , Modelos Estatísticos , Insuficiência Renal/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Carbapenêmicos/administração & dosagem , Carbapenêmicos/sangue , Simulação por Computador , Doripenem , Humanos , Japão , Pessoa de Meia-Idade , Método de Monte Carlo , Adulto Jovem
5.
Clin Drug Investig ; 43(10): 785-797, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37798608

RESUMO

BACKGROUND: A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use. OBJECTIVES: The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state. METHODS: A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies. RESULTS: The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7-58.9 h across all cohorts. The Cmax and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C24) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to Cmax in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (Cmax and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved. CONCLUSION: Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C24 exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021.


Assuntos
COVID-19 , Adulto , Humanos , Masculino , Feminino , Idoso , Estudos Cross-Over , Comprimidos , Área Sob a Curva , Administração Oral , Voluntários Saudáveis
6.
Clin Drug Investig ; 43(5): 335-346, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37171749

RESUMO

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.


Assuntos
COVID-19 , Inibidores do Citocromo P-450 CYP3A , Indazóis , Adulto , Humanos , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Dexametasona/farmacocinética , Interações Medicamentosas , População do Leste Asiático , Indazóis/efeitos adversos , Midazolam/farmacocinética , Prednisolona/farmacocinética , SARS-CoV-2 , Triazinas/efeitos adversos , Triazóis/efeitos adversos
7.
J Clin Pharmacol ; 63(8): 918-927, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37043676

RESUMO

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.


Assuntos
COVID-19 , Metformina , Transportadores de Ânions Orgânicos , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , SARS-CoV-2 , Rosuvastatina Cálcica/farmacocinética , Inibidores de Proteases , Proteínas de Neoplasias/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Interações Medicamentosas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Digoxina/farmacocinética , Inibidores Enzimáticos , Transportador 1 de Cátions Orgânicos , Metformina/farmacocinética , Transporte Biológico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
8.
Neuropsychopharmacol Rep ; 43(3): 346-358, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37366077

RESUMO

AIM: This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects. METHODS: This single-center study consisted of three parts. In Part A (randomized, double-blind), the safety, tolerability, and pharmacokinetics of single dose and 7-day consecutive multiple doses of zuranolone 10, 20, and 30 mg and placebo were assessed in 36 Japanese adults, 24 White adults, and 12 Japanese elderly (aged 65-75 years) subjects. In Part B (randomized, open-label, crossover), the effect of food intake on the pharmacokinetics and safety of single-dose zuranolone 30 mg was evaluated in 12 Japanese adults. In Part C (randomized, double-blind, crossover), the effects of single-dose zuranolone 10 and 30 mg and placebo on electroencephalography parameters were evaluated in eight Japanese adults. RESULTS: Single and multiple doses of zuranolone were safe and well tolerated in all subjects. Linear pharmacokinetics were observed in the studied dose range. Time to steady-state plasma concentration was within 72 h for Japanese and White adults. Pharmacokinetic profiles were comparable between Japanese and White adults and between Japanese adults and Japanese elderly subjects. Plasma exposures of zuranolone were greater in the fed versus fasted state. Single-dose zuranolone 30 mg increased low-beta electroencephalography power. CONCLUSION: In healthy Japanese subjects, zuranolone was well tolerated; pharmacokinetic profile was unaffected by ethnicity or age; plasma exposures were greater in the fed state. The increased low-beta electroencephalography power with the 30-mg dose is consistent with γ-aminobutyric acid receptor type A activation by zuranolone.


Assuntos
População do Leste Asiático , Pirazóis , População Branca , Adulto , Idoso , Humanos , Voluntários Saudáveis , Pirazóis/farmacocinética
9.
Int J Chron Obstruct Pulmon Dis ; 18: 1047-1055, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37304764

RESUMO

Purpose: Disease probability measure (DPM) is a useful voxel-wise imaging assessment of gas-trapping and emphysematous lesions in patients with chronic obstructive pulmonary disease (COPD). To elucidate the progression of COPD, we performed a cluster analysis using the following DPM parameters: normal (DPMNormal), gas-trapping (DPMGasTrap), and emphysematous lesions (DPMEmph). Our findings revealed the characteristics of each cluster and the 3-year disease progression using imaging parameters. Patients and Methods: Inspiratory and expiratory chest computed tomography (CT) images of 131 patients with COPD were examined, of which 84 were followed up for 3 years. The percentage of low attenuation volume (LAV%) and the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10) were quantitatively measured using inspiratory chest CT. A hierarchical cluster analysis was performed using the DPM parameters at baseline. Five clusters were named according to the dominant DPM parameters: normal (NL), normal-GasTrap (NL-GT), GasTrap (GT), GasTrap-Emphysema (GT-EM), and Emphysema (EM). Results: Women were predominantly diagnosed with GT. Forced expiratory volume in 1 s gradually decreased in the following order: NL, NL-GT, GT, GT-EM, and EM. DPMEmph correlated well with LAV%. Four clusters other than NL showed significantly higher values of √Aaw at Pi10 than NL; however, no significant differences were observed among them. In all clusters, DPMEmph increased after 3 years. DPMNormal only increased in the GT cluster. Conclusion: Clusters using DPM parameters may reflect the characteristics of COPD and help understand the pathophysiology of the disease.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise por Conglomerados , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Inalação , Expiração
10.
Drug Metab Pharmacokinet ; 35(6): 548-554, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33082099

RESUMO

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d-amphetamine concentrations from pediatric patients (6-17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d-amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d-amphetamine.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacocinética , Dimesilato de Lisdexanfetamina/farmacocinética , Modelos Biológicos , Pró-Fármacos/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/sangue , Criança , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Japão , Dimesilato de Lisdexanfetamina/administração & dosagem , Dimesilato de Lisdexanfetamina/sangue , Masculino , Pró-Fármacos/administração & dosagem , Estados Unidos
11.
Drug Metab Pharmacokinet ; 35(1): 145-150, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31969257

RESUMO

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT>MIC against MIC of 2 µg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants.


Assuntos
Antibacterianos/farmacocinética , Doripenem/farmacocinética , Modelos Biológicos , Antibacterianos/sangue , Doripenem/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Método de Monte Carlo
12.
Neuropsychopharmacol Rep ; 40(1): 16-29, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31765110

RESUMO

AIM: To assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults. METHODS: A phase 1, double-blind, randomized, placebo-controlled, single- and multiple-dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4-8), 50 mg/d (Days 9-13), 70 mg/d (Days 14-18), or matching placebo. Pharmacokinetic parameters for lisdexamfetamine and d-amphetamine were estimated by noncompartmental analysis. RESULTS: Fifteen Japanese and 19 Caucasian subjects were enrolled and randomized. The lisdexamfetamine and d-amphetamine plasma concentration-time curves were similar for both ethnic groups following single and multiple doses. Mean area under the concentration-time curves for d-amphetamine were higher (by 11%-15%) in Japanese than Caucasian subjects following multiple dosing of lisdexamfetamine. Mean bodyweight was 17% lower in Japanese than Caucasian subjects. Weight-corrected means for oral clearance were similar in both ethnic groups, with no unexpected accumulation of d-amphetamine. Lisdexamfetamine was generally well tolerated by both ethnic groups, with no serious adverse events reported. The 10/12 Japanese and 11/16 Caucasian subjects who received lisdexamfetamine completed the study; two Japanese and three Caucasian subjects discontinued due to adverse events. Most adverse events were of mild severity. CONCLUSION: Pharmacokinetics were generally similar for Japanese and Caucasian subjects; the minor differences observed were likely due to bodyweight differences in the two ethnic groups. Lisdexamfetamine was generally well tolerated. Adverse events were consistent with the established safety profile of lisdexamfetamine and were similar in both ethnic groups.


Assuntos
Povo Asiático , Estimulantes do Sistema Nervoso Central/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , População Branca , Adolescente , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/farmacocinética , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Japão , Dimesilato de Lisdexanfetamina/administração & dosagem , Dimesilato de Lisdexanfetamina/efeitos adversos , Dimesilato de Lisdexanfetamina/farmacocinética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
13.
J Pharm Sci ; 108(9): 3099-3105, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30974120

RESUMO

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax®, Doribax®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 µg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.


Assuntos
Antibacterianos/farmacocinética , Variação Biológica da População , Doripenem/farmacocinética , Cálculos da Dosagem de Medicamento , Modelos Biológicos , Adolescente , Antibacterianos/administração & dosagem , Peso Corporal , Criança , Pré-Escolar , Ensaios Clínicos Fase III como Assunto , Simulação por Computador , Doripenem/administração & dosagem , Esquema de Medicação , Feminino , Infecções por Haemophilus/tratamento farmacológico , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/efeitos dos fármacos , Humanos , Lactente , Infusões Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Estudos Multicêntricos como Assunto , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/microbiologia , Fatores Sexuais , Streptococcus pneumoniae/efeitos dos fármacos
14.
Drug Metab Pharmacokinet ; 34(6): 365-371, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563330

RESUMO

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6-17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Guanfacina/sangue , Guanfacina/farmacocinética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Criança , Feminino , Humanos , Masculino
15.
Int J Chron Obstruct Pulmon Dis ; 14: 2971-2977, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31908445

RESUMO

Purpose: The forced oscillation technique (FOT) is a non-invasive method to measure respiratory impedance, the respiratory resistance (Rrs) and reactance (Xrs). The disease probability measure (DPM) is a useful computed tomography (CT) imaging variable for the assessment of gas trapping and emphysema in patients with chronic obstructive pulmonary disease (COPD) using pairs of inspiratory and expiratory CT images. We aimed to develop FOT-based phenotypes and determine whether the phenotypes and their imaging characteristics could facilitate the understanding of COPD pathophysiology. Patients and methods: FOT and spirometry were examined in 164 COPD patients and 22 non-COPD smokers. COPD patients were divided into four FOT-based phenotypes (NL, normal group; RD, resistance-dominant group; XD, reactance-dominant group; and MIX, mixed group) based on the 3rd quartile values of R5 (Rrs at 5Hz) and X5 (Xrs at 5Hz) in the non-COPD group. The emphysematous lesions and the airway lesions were quantitatively assessed in CT images by low attenuation volume and the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10), respectively. DPM imaging analysis was also performed in 131 COPD patients. We investigated the differences in COPD parameters between the FOT-based phenotypes. Results: √Aaw at Pi10 were significantly higher in the RD, XD, and MIX groups than in the NL group. The XD group showed lower pulmonary function and higher dyspnea scores than the RD group. No significant changes in DPM values were observed between the RD and the NL groups. The gas-trapping area was significantly higher in the XD group than in the NL group. The MIX group showed the highest dyspnea score, most emphysematous lesions, and the lowest forced expiratory volume in 1 s % predicted value. Conclusion: The FOT-based phenotyping may be useful to assess pathophysiological changes of COPD with CT assessments.


Assuntos
Resistência das Vias Respiratórias/fisiologia , Impedância Elétrica , Oscilometria/métodos , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Variação Biológica da População/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/fisiopatologia , Reprodutibilidade dos Testes , Testes de Função Respiratória/métodos , Tomografia Computadorizada por Raios X/métodos
16.
Masui ; 56(10): 1168-73, 2007 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-17966620

RESUMO

BACKGROUND: According to the instruction manual, the sniffing position (SP) and the slight lateral approach (SLA) are the recommended insertion methods using Proseal laryngeal mask airway (PLMA). However, the efficacy of these methods has not been assessed. METHODS: The incidence and the reason of the insertion with difficulty were assessed in 50 adult patients. And then, the efficacy of these methods in the patient with insertion difficulty was studied. RESULTS: Establishment of the airway was unsuccessful in 10 patients at first attempt. The commonest reason of unsuccessful attempt was failure to slide PLMA into the pharynx. The insertion was successful and patent airway was obtained using Full-SP and SLA in 8 of the 10 patients. CONCLUSIONS: It was suggested that Full-SP and SLA were useful to place PLMA in patients with insertion difficulty.


Assuntos
Intubação Intratraqueal/métodos , Máscaras Laríngeas , Idoso , Feminino , Humanos , Incidência , Intubação Intratraqueal/estatística & dados numéricos , Máscaras Laríngeas/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Postura/fisiologia
17.
Clin Drug Investig ; 37(8): 745-753, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28421383

RESUMO

BACKGROUND AND OBJECTIVE: Guanfacine extended-release (guanfacine XR) could be a useful treatment option for children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). As an initial step in the development in Japan, the pharmacokinetics, safety and tolerability were assessed in healthy Japanese and non-Hispanic Caucasian adults. METHODS: A Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-oral dose escalation study of guanfacine XR was conducted. Healthy Japanese and Caucasian subjects received guanfacine XR 1 mg orally in the morning on Day 1. Following safety assessments, subjects subsequently received guanfacine XR 1 mg (Days 4-8), 2 mg (Days 9-13), 3 mg (Days 14-18), and 4 mg (Days 19-23) once daily, followed by a taper-down period. Single- and multiple-dose pharmacokinetic parameters were estimated based on plasma concentration-time data and urine concentration data of guanfacine by non-compartmental analysis. RESULTS: A total of 30 male subjects (15 Japanese and 15 Caucasian, active:placebo = 12:3) were enrolled. Of those receiving guanfacine XR, 11/12 (91.7%) subjects in each active drug group completed the study. Following multiple doses, the mean area under the plasma concentration-time curves of guanfacine were 9-22% greater for Caucasian subjects than Japanese subjects in the 1-3 mg dose range and 54% greater for the 4 mg. Guanfacine XR was generally well tolerated by both ethnic groups, with most adverse events being mild in both groups. There were no serious or severe adverse events during the study and no adverse events led to withdrawal from the study. CONCLUSIONS: Exposure to guanfacine in Japanese subjects tended to be lower than in Caucasian subjects. Guanfacine XR was generally well tolerated and safety profiles were similar for Japanese and Caucasian subjects.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Guanfacina/administração & dosagem , Adulto , Preparações de Ação Retardada , Método Duplo-Cego , Guanfacina/efeitos adversos , Guanfacina/farmacocinética , Humanos , Japão , Masculino , Pessoa de Meia-Idade
18.
Anesth Analg ; 102(4): 1285-6, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16551938

RESUMO

Gerstmann-Sträussler-Scheinker Syndrome (GSS) is a rare, infectious syndrome related to a mutation in the prion protein. A 60-yr-old, 152-cm, 31-kg woman with GSS was scheduled for open gastrostomy. This is the first report about an anesthetic experience in a patient with GSS. We describe our experience and precautions in the anesthetic management of a GSS patient.


Assuntos
Anestesia/métodos , Doença de Gerstmann-Straussler-Scheinker/cirurgia , Mutação/genética , Príons/genética , Obstrução das Vias Respiratórias/prevenção & controle , Contaminação de Equipamentos/prevenção & controle , Feminino , Doença de Gerstmann-Straussler-Scheinker/genética , Humanos , Intubação Intratraqueal/instrumentação , Intubação Intratraqueal/métodos , Pessoa de Meia-Idade
19.
Masui ; 55(10): 1266-9, 2006 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-17051992

RESUMO

A 75-year-old man had neck sprain by traffic accident. He had headache but not orthostatic at first. He also had dysesthesia and pain of upper limbs, neck pain, and nausea. His symptoms vanished immediately after 10 ml bolus thoracic epidural injection of normal saline for about one hour. Succeeding continuous epidural injection of normal saline (10 ml x h(-1)) made him symptom free until stopping injection. If headache of a patient vanished after epidural normal saline injection, a diagnosis of intracranial hypotension syndrome can be made. This patient became pain free after one trial of cervical epidural blood patch of 12 ml. Quantity of blood to be injected into the cervical epidural space can be decided by flood of injected blood from thoracic epidural vent tapped in advance.


Assuntos
Hipotensão Intracraniana/diagnóstico , Cloreto de Sódio/administração & dosagem , Idoso , Placa de Sangue Epidural , Humanos , Injeções Epidurais , Hipotensão Intracraniana/terapia , Masculino , Resultado do Tratamento
20.
J Pharm Sci ; 104(9): 3194-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25821174

RESUMO

The aim of this paper was to predict the pharmacokinetics of doripenem in pediatrics from adult pharmacokinetic data and to investigate dosing regimens in pediatrics using Monte-Carlo pharmacokinetics/pharmacodynamics (PK/PD) simulations prior to the initiation of pediatric clinical trials. The pharmacokinetics in pediatrics was predicted by using a previously reported approach for ß-lactam antibiotics. Monte-Carlo simulation was employed to assess dosing regimens in pediatrics based on the predicted pharmacokinetic profiles and the minimum inhibitory concentration (MIC) distributions of Haemophilus influenzae and Streptococcus pneumoniae, which frequently cause infectious pediatric diseases. The probabilities of attaining target time above MIC (40%T>MIC) were calculated for dosing regimens of 1-30 mg/kg with two or three times daily dosing (TID) based on simulations of 5000 pediatric patients and MICs. The results suggested 15 and 5 mg/kg TID would give approximately 90% or more probability of target attainment against Haemophilus influenzae and Streptococcus pneumoniae, respectively. The pediatric phase 3 study confirmed that pharmacokinetics in pediatrics could be well predicted by this method, indicating that the dosing regimen had been appropriately selected. The framework of dose selection for pediatric clinical trials based on predictions of pharmacokinetic profiles and PK/PD indices should be applicable to the development of other ß-lactam antibiotics for pediatric use.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacocinética , Carbapenêmicos/uso terapêutico , Adulto , Criança , Doripenem , Haemophilus influenzae/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana/métodos , Método de Monte Carlo , Streptococcus pneumoniae/efeitos dos fármacos
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