RESUMO
PURPOSE: S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. METHODS: In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. RESULTS: S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. CONCLUSIONS: Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.
Assuntos
Indutores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Lopinavir/farmacologia , Modelos Biológicos , Ritonavir/farmacologia , Varfarina/farmacologia , Fatores Etários , Área Sob a Curva , Teorema de Bayes , Citocromo P-450 CYP2C9/genética , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Fenótipo , Fatores Sexuais , Varfarina/administração & dosagemRESUMO
Despite a number of studies reporting that ertapenem pharmacokinetic parameters differ considerably in obese patients from those in healthy volunteers, functions describing the relationships between this agent's pharmacokinetics and indicators of body size have not been developed. The aim of this analysis was to develop an ertapenem population pharmacokinetic model using data from a previously described study in normal-weight, obese, and morbidly obese healthy volunteers. A single ertapenem 1-g dose administered intravenously was evaluated in 30 subjects within different body mass index (BMI) categories. The population pharmacokinetic model was developed using the first-order conditional estimation method with interaction (FOCE-I) algorithm within NONMEM. The ability of age, sex, renal function, and various body size measures (total body weight, height, body mass index, ideal body weight, fat-free mass, and body surface area [BSA]) to explain a portion of the interindividual variability on select pharmacokinetic parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The data were best described using a linear three-compartment model with total body weight as a covariate on clearance (CL = 1.79 · [weight/95.90]0.278) and BSA as a covariate on central volume (Vc = 4.76 · [BSA/2.06]1.86). After accounting for fixed effects, the estimated interindividual variability was very low (<10% for all clearance and volume terms). Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. Using the developed population pharmacokinetic model and simulation, reliable estimates of ertapenem serum exposures, which can be utilized to evaluate various dosing regimens in subjects with a wide range of body sizes, are expected.
Assuntos
Ertapenem/farmacocinética , Adulto , Algoritmos , Índice de Massa Corporal , Tamanho Corporal , Peso Corporal/fisiologia , Carbapenêmicos/sangue , Carbapenêmicos/farmacocinética , Ertapenem/sangue , Feminino , Humanos , Masculino , FarmacocinéticaRESUMO
BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.
Assuntos
Citocromo P-450 CYP2C19/metabolismo , Omeprazol/farmacocinética , Tamanho da Amostra , Adulto , Antiulcerosos/sangue , Antiulcerosos/farmacocinética , Simulação por Computador , Citocromo P-450 CYP2C19/genética , Genótipo , Voluntários Saudáveis , Humanos , Modelos Biológicos , Omeprazol/sangueRESUMO
BACKGROUND: Phenotyping cytochrome P450 (CYP) 2C9 activity using S-warfarin has routinely required extensive blood sampling over at least 96 hours after dose to estimate the area under the concentration time curve from zero to infinity (AUC). Alternatively, S-warfarin limited sampling models (LSMs) using one or 2 concentration timepoints have been proposed to estimate AUC. This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced-stage cancer patients. METHODS: Plasma S-warfarin concentrations from healthy adults (n = 92) and in advanced-stage cancer patients (n = 22) were obtained from 6 published studies where a single 10 mg dose of oral warfarin was administered at CYP2C9 baseline and induction conditions. S-warfarin observed AUC was determined by noncompartmental analysis, whereas estimated AUC was calculated from the LSMs. Bias and precision were assessed by percent mean prediction error, percent mean absolute error, and percent root mean square error. RESULTS: Different results were observed for S-warfarin LSMs in estimating CYP2C9 baseline activity, with most studies resulting in unacceptable bias and precision. The percent mean prediction error, percent mean absolute error, and/or percent root mean square error exceeded acceptable limits for LSMs in patients with advanced-stage cancer and during CYP2C9 induction with lopinavir/ritonavir. CONCLUSIONS: The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs.
Assuntos
Anticoagulantes/farmacocinética , Citocromo P-450 CYP2C9/genética , Monitoramento de Medicamentos/métodos , Varfarina/farmacocinética , Administração Oral , Adulto , Idoso , Anticoagulantes/administração & dosagem , Área Sob a Curva , Viés , Coleta de Amostras Sanguíneas , Estudos de Casos e Controles , Citocromo P-450 CYP2C9/biossíntese , Indução Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Neoplasias/patologia , Fenótipo , Estudos Retrospectivos , Fatores de Tempo , Varfarina/administração & dosagem , Adulto JovemRESUMO
Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m(2), respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051-1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance.
Assuntos
Aminoglicosídeos/farmacocinética , Obesidade/sangue , Magreza/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Feminino , Gentamicinas/farmacocinética , Taxa de Filtração Glomerular , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tobramicina/farmacocinética , Adulto JovemRESUMO
BACKGROUND: There is a worldwide obesity epidemic, but lack of a simple method, applicable for research or clinical use, to identify individuals at high risk of weight gain. Therefore, the relationship of self-rated health and 10-year percent weight change was evaluated to determine if self-rated health would predict weight change. METHODS: From 1990 to 2008, adults aged 30, 40, 50 and 60 years were invited to health surveys that included self-rated health and measured weight and height. ANOVA was used to evaluate the relationship of 10-year percent weight change and self-rated health. RESULTS: The study population consisted of 29,207 participants (46.5% men). There was no relationship between baseline self-rated health and 10-year percent weight change for middle-aged men or women. CONCLUSIONS: Self-rated health is not able to predict weight change over a 10-year period in this age group.
Assuntos
Nível de Saúde , Inquéritos Epidemiológicos , Autorrelato , Aumento de Peso , Adulto , Feminino , Previsões , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Use of US Food and Drug Administration-approved substances of abuse has innate risks due to pharmacologic and pharmacokinetic properties of the medications, but the risk when using nonapproved drug products is much greater. Unbeknownst to the user, the dose of active ingredients in substances of abuse can vary substantially between different products because of manufacturing practices or improper storage. Even naturally occurring substances of abuse can have extensive dosage variability because of effects of the growing season and conditions, or differences in harvesting, storage, or manufacture of the finished products. Many illicit substances are adulterated, to make up for intentional underdosing or to enhance the effect of the intended active ingredient. These adulterants can be dangerous and produce direct cardiovascular, neurologic, hematologic, or dermatologic reactions or obscure adverse effects. Finally, an illicit substance can be contaminated or substituted for another one during its manufacture, leading to differences in adverse events, adverse event severity, or the drug interaction profile. Substances can be contaminated with microbes that induce infections or heavy metals that can damage organs or cause cancer. This milieu of undisclosed substances can also induce drug interactions. For reasons that are discussed, individuals who use substances of abuse are at increased risk of morbidity or mortality if they develop coronavirus disease 2019. Health professionals who treat patients with acute, urgent events associated with substances of abuse, or those treating the chronic manifestations of addiction, need to appreciate the complex and variable composition of substances of abuse and their potential health effects.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Drogas Ilícitas/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações , COVID-19/mortalidade , Interações Medicamentosas/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Humanos , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Estados Unidos , United States Food and Drug AdministrationRESUMO
Oliceridine is a G protein-biased ligand at the µ-opioid receptor in development for treatment of moderate to severe acute pain. A phase 1, open-label, single-dose study investigated the pharmacokinetics and safety of oliceridine 0.5 mg intravenous (IV) in subjects with end-stage renal disease (ESRD, n = 9) versus 1 mg in healthy controls (n = 8). A second phase 1, open-label, single-dose study investigated the pharmacokinetics and safety of a 0.5-mg IV dose in hepatic impairment (mild, n = 10; moderate, n = 10; severe, n = 6) versus 1 mg in healthy controls (n = 8). The controls were sex and age (±10 years) matched. In ESRD versus healthy subjects, no difference in clearance was observed between ESRD patients and subjects with normal renal function. Oliceridine clearance and AUC were not affected by hepatic impairment. Half-life (hours; GM [%CV]) increased in subjects with moderate (4.3 [44.1]) and severe (5.8 [41.2]) impairment versus mild impairment (2.6 [20.0]) and healthy subjects (2.1 [11.3]). Volume of distribution was increased with the degree of hepatic impairment. All adverse events were mild and generally consistent with the known safety profile of oliceridine. No dose adjustment is needed in patients with renal impairment or in patients with mild or moderate hepatic impairment. Initial dose reduction should be considered in severe hepatic impairment, and patients may require fewer doses of oliceridine due to the longer half-life observed in these patients.
Assuntos
Dor Aguda/tratamento farmacológico , Receptores Opioides mu/metabolismo , Compostos de Espiro/farmacocinética , Tiofenos/farmacocinética , Administração Intravenosa , Adulto , Estudos de Casos e Controles , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Ligantes , Hepatopatias/complicações , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Segurança , Índice de Gravidade de Doença , Compostos de Espiro/administração & dosagem , Compostos de Espiro/sangue , Compostos de Espiro/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/sangue , Tiofenos/uso terapêuticoRESUMO
Although the medical profession strives for safe prescribing, most medications are unique challenges even when prescribed by an experienced provider. In this article we discuss the pitfalls associated with drug interactions between commonly used antibiotics and anticoagulants, the complexities associated with the administration of novel reversible anticoagulants, the often-overlooked severe adverse drug reactions from commonly used classes of medications such as corticosteroids, the nuances of managing an acetaminophen overdose, and uncommon yet serious adverse events associated with the use of contraceptive hormone drugs.
Assuntos
Acetaminofen/efeitos adversos , Corticosteroides/efeitos adversos , Antibacterianos/efeitos adversos , Anticoagulantes/efeitos adversos , Anticoncepcionais Orais Hormonais/efeitos adversos , Adolescente , Idoso , Interações Medicamentosas , Overdose de Drogas , Feminino , Humanos , Internato e Residência , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Teorema de Bayes , Disponibilidade Biológica , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Cinética , Masculino , Midazolam/administração & dosagemRESUMO
STUDY OBJECTIVE: To compare the pharmacodynamics of uniform versus nonuniform warfarin dosages. DESIGN: Prospective, randomized, crossover study. SETTING: Anticoagulation clinic. SUBJECTS: Twenty healthy subjects who had the extensive metabolizer cytochrome P450 (CYP) genotype of 2C9*1/*1 or CYP2C9*1/*3. INTERVENTION: Subjects received either warfarin 5.75 mg once/day (two 1-mg tablets plus one and a half 2.5-mg tablets) as part of the uniform dosage group or warfarin 7.5 mg/day on Mondays and Fridays and 5 mg/day on each of the remaining days of the week as part of the nonuniform dosage group. Subjects received the first regimen for 17 days, had a 2-week washout period, and then were switched to the other regimen for another 17 days. MEASUREMENTS AND MAIN RESULTS: During both treatment periods, international normalized ratios (INRs) were checked daily using a fingerstick method. Any changes in concomitant drug therapy, including over-the-counter and supplement products, as well as health status were recorded. The Scheffe post hoc test revealed no significant differences in mean INR values obtained during receipt of the two dosage regimens. In both dosage groups, variation in the INR became more pronounced as INR values increased. No adverse events (i.e., major or minor bleeding) or changes in drug therapy were reported during the study. CONCLUSION: Our findings suggest that it is safe to use a nonuniform dosage regimen of warfarin to reach a target INR range. With both uniform and nonuniform regimens, close monitoring remains important to ensure that patients remain within the desired INR range.
Assuntos
Anticoagulantes/administração & dosagem , Varfarina/administração & dosagem , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Prospectivos , Varfarina/farmacologiaRESUMO
This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical procedures or anesthesia is not discussed. Basic pharmacokinetic and pharmacodynamic properties of opioids are reviewed. The safe and effective use of opioids, including clinical assessment and treatment plan, equianalgesic dosing, opioid rotation, opioid risks and side effects, and clinical adherence monitoring are discussed. Individualized opioid use can be a safe and effective component of a patient-specific multimodal treatment plan for acute or chronic pain. Adverse effects and risks can be prevented or effectively managed when anticipated and recognized. The article is followed by 4 clinical vignettes with discussions.
Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Tomada de Decisões , Tolerância a Medicamentos , Humanos , Adesão à Medicação , Transtornos Relacionados ao Uso de Opioides , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de SubstânciasRESUMO
Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.
Assuntos
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Adulto , Área Sob a Curva , Feminino , Humanos , Hipnóticos e Sedativos/metabolismo , Masculino , Midazolam/metabolismo , Pessoa de Meia-Idade , Modelos BiológicosRESUMO
PURPOSE: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.
Assuntos
Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias Encefálicas/sangue , Paclitaxel/farmacocinética , Tamoxifeno/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Sinergismo Farmacológico , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Obesity has primarily been addressed with interventions to promote weight loss and these have been largely unsuccessful. Primary prevention of obesity through support of weight maintenance may be a preferable strategy although to date this has not been the main focus of public health interventions. The aim of this study is to characterize who is not gaining weight during a 10 year period in Sweden. METHODS: Cross-sectional and longitudinal studies were conducted in adults aged 30, 40, 50 and 60 years during the Västerbotten Intervention Programme in Sweden. Height, weight, demographics and selected cardiovascular risk factors were collected on each participant. Prevalences of obesity were calculated for the 40, 50 and 60 year olds from the cross-sectional studies between 1990 and 2004. In the longitudinal study, 10-year non-gain (lost weight or maintained body weight within 3% of baseline weight) or weight gain (> or = 3%) was calculated for individuals aged 30, 40, or 50 years at baseline. A multivariate logistic regression model was built to predict weight non-gain. RESULTS: There were 82,927 adults included in the cross-sectional studies which had an average annual participation rate of 63%. Prevalence of obesity [body mass index (BMI) in kg/m2 > or = 30] increased from 9.4% in 1990 to 17.5% in 2004, and 60 year olds had the highest prevalence of obesity. 14,867 adults with a BMI of 18.5-29.9 at baseline participated in the longitudinal surveys which had a participation rate of 74%. 5242 adults (35.3%) were categorized as non-gainers. Older age, being female, classified as overweight by baseline BMI, later survey year, baseline diagnosis of diabetes, and lack of snuff use increased the chances of not gaining weight. CONCLUSION: Educational efforts should be broadened to include those adults who are usually considered to be at low risk for weight gain--younger individuals, those of normal body weight, and those without health conditions (e.g. diabetes type 2) and cardiovascular risk factors--as these are the individuals who are least likely to maintain their body weight over a 10 year period. The importance of focusing obesity prevention efforts on such individuals has not been widely recognized.
Assuntos
Peso Corporal , Educação em Saúde/organização & administração , Obesidade/epidemiologia , Obesidade/prevenção & controle , Adulto , Distribuição por Idade , Análise de Variância , Composição Corporal , Índice de Massa Corporal , Estudos Transversais , Exercício Físico , Feminino , Humanos , Incidência , Estilo de Vida , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Participação do Paciente , Prevenção Primária/organização & administração , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Suécia/epidemiologiaRESUMO
OBJECTIVE: Our objective was to compare simvastatin with the validated probe midazolam in the assessment of cytochrome P450 (CYP) 3A activity. METHODS: This study used an open-label, fixed-sequential, 3-way crossover study design. Nineteen subjects received oral doses of 0.075 mg/kg midazolam and 40 mg simvastatin during 3 phases (baseline, after inhibition with 400 mg ketoconazole for 10 days, and after induction with 600 mg rifampin [INN, rifampicin] for 9 days). Serial plasma concentrations of midazolam and simvastatin were obtained. Oral clearances of midazolam and simvastatin were compared. RESULTS: Oral midazolam clearance decreased after pretreatment with ketoconazole (from a geometric mean of 25 mL x min(-1) x kg(-1) [range, 12-57 mL x min(-1) x kg(-1)] to 2.7 mL x min(-1) x kg(-1) [range, 1.2-8.5 mL x min(-1) x kg(-1)], P < .001) and increased after pretreatment with rifampin (to a geometric mean of 203 mL x min(-1) x kg(-1) [range, 125-371 mL x min(-1) x kg(-1)], P < .001). Oral simvastatin clearance decreased after ketoconazole (from a geometric mean of 312 mL x min(-1) x kg(-1) [range, 151-1478 mL x min(-1) x kg(-1)] to 25 mL x min(-1) x kg(-1) [range, 8.0-147 mL x min(-1) x kg(-1)], P < .001) and increased after rifampin (to a geometric mean of 3536 mL x min(-1) x kg(-1) [range, 413-10,329 mL x min(-1) x kg(-1)], P < .001). The change in simvastatin clearance was highly variable from baseline to inhibition (6- to 33-fold decrease) and from baseline to induction (2- to 39-fold increase) compared with midazolam (7- to 18-fold decrease during inhibition and 4- to 12-fold increase during induction). Midazolam and simvastatin oral clearances were correlated for all study phases (r = 0.5 and P = .03 for baseline and r = 0.53 and P = .02 for inhibition) but were weakest for induction (r = -0.031, P = .22). The area under the concentration-time curve inhibitory ratio for midazolam was 9.4 versus 12.4 for simvastatin (r = 0.3, P = .03). CONCLUSIONS: Compared with midazolam, simvastatin is a nonvalidated, suboptimal probe for studying CYP3A drug interactions because of its lack of CYP3A specificity.
Assuntos
Anestésicos Intravenosos/farmacocinética , Anticolesterolemiantes/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Sinvastatina/farmacocinética , Administração Oral , Adulto , Anestésicos Intravenosos/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Masculino , Midazolam/administração & dosagem , Sinvastatina/administração & dosagemRESUMO
BACKGROUND: Studies examining sex differences in CYP3A activity have produced conflicting results. Our objective is to investigate whether sex differences exist in CYP3A activity as assessed by intravenous (IV) or oral midazolam pharmacokinetic analysis in healthy volunteers. METHODS: Data from 13 previous studies were used. A single dose of IV midazolam (0.025 mg/kg) was administered to 66 white adults (37 women and 29 men; mean age, 36.3+/-7.7 years). A single dose of oral midazolam, 0.075 mg/kg (5 studies), 0.15 mg/kg (1 study), or 5 mg (1 study), was administered to 72 adults (71 white and 1 Asian; 37 women and 35 men; mean age, 38.3+/-8.9 years). Pharmacokinetic parameters were determined via population methods by use of a nonparametric adaptive grid program and a 2-compartment IV and 1-compartment oral absorption model. The maximum a posteriori probability Bayesian method was used to estimate each subject's pharmacokinetic parameters. Monte Carlo simulation was performed to determine the probability distribution of the area under the concentration-time curves (AUCs). RESULTS: Women exhibited 11% higher mean weight-corrected total body midazolam clearance and 28% higher oral clearance compared with men (PAssuntos
Citocromo P-450 CYP3A/metabolismo
, Midazolam/farmacocinética
, Administração Oral
, Adulto
, Ansiolíticos/administração & dosagem
, Ansiolíticos/farmacocinética
, Área Sob a Curva
, Teorema de Bayes
, Ensaios Clínicos como Assunto
, Feminino
, Humanos
, Injeções Intravenosas
, Masculino
, Taxa de Depuração Metabólica
, Midazolam/administração & dosagem
, Método de Monte Carlo
, Fatores Sexuais
RESUMO
Oral midazolam is used as a phenotyping probe for cytochrome P450 (CYP) 3A activity and requires multiple plasma samples to measure drug exposure. Limited sampling is a useful strategy for optimizing sampling and reducing costs and labor. We studied limited sampling models using multiple linear regressions to predict the area under the concentration versus time curve (AUC) of midazolam using either midazolam plasma concentrations or the ratio of 1-hydroxymidazolam (1-OH MDZ) to midazolam plasma concentrations. CYP3A baseline activity data for oral midazolam from previous studies were used (45 healthy adults for models using midazolam plasma concentrations and 41 healthy adults for models using the ratios of 1-OH MDZ to midazolam plasma concentrations). Limited sampling models were derived, validated, and evaluated for precision and bias. Two equations using the time points at 0.5 and 6 hours and 0.5, 2, and 6 hours were acceptable and predictive of midazolam AUC using midazolam plasma concentrations. No 1-OH MDZ to midazolam plasma concentration ratios accurately predicted midazolam AUC.