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1.
Eur J Clin Pharmacol ; 77(9): 1349-1356, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33754183

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 & dosagem
2.
Artigo em Inglês | MEDLINE | ID: mdl-30061283

RESUMO

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 , Farmacocinética
3.
Ther Drug Monit ; 40(6): 754-758, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30045358

RESUMO

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/sangue
4.
Ther Drug Monit ; 38(3): 383-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26818625

RESUMO

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 Jovem
5.
Antimicrob Agents Chemother ; 55(9): 4006-11, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21670189

RESUMO

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 Jovem
6.
Alcohol ; 78: 51-56, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30660599

RESUMO

AIMS: To identify the extent to which patients admitted to a general hospital in Vietnam meet the criteria for risky alcohol drinking, alcohol use disorder (AUD), and alcohol withdrawal syndrome (AWS), describe problems and behavior of alcohol use such as types and quantity of alcohol drinking in a hospitalized population in Vietnam, and investigate the association among age, disease-related factors, and alcohol consumption with AWS. METHODS: This study was conducted prospectively in 1340 patients admitted to a general hospital. All patients were screened for risky alcohol drinking. Risky alcohol drinkers were assessed by using the Alcohol Use Disorder Identification Test (AUDIT) to identify AUD patients. The diagnosis of AWS was based on criteria defined by Diagnostic and Statistical Manual of Mental Disorders, version 5. The AWS scale was used to quantitate AWS severity level. RESULTS: Prevalence of risky alcohol drinkers, AUD patients, and AWS patients among hospitalized patients was 15.5%, 13.1%, and 7.3%, respectively. All of the AUD and AWS patients were male. The majority of risky alcohol drinkers, patients with AUD, and patients with AWS were 40-60-year-old men. Almost all patients (98.3%) drank homemade alcohol. Hospitalized patients were more likely to develop AWS if they had liver disease or past experience with AWS. CONCLUSIONS: AUD and AWS are common in hospitalized patients. Formulating a protocol to identify and care for patients with alcohol-related disorders is urgent.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Comportamentos de Risco à Saúde , Síndrome de Abstinência a Substâncias/epidemiologia , Adulto , Idoso , Estudos Transversais , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Hospitalização , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Vietnã/epidemiologia
7.
J Clin Pharmacol ; 59(11): 1495-1504, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31051051

RESUMO

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 & dosagem
9.
Pharmacotherapy ; 28(6): 707-11, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18503398

RESUMO

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/farmacologia
10.
J Clin Pharmacol ; 58(9): 1205-1213, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29663428

RESUMO

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 Biológicos
11.
Clin Infect Dis ; 45(6): 753-60, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17712761

RESUMO

Gram-negative organisms have become increasingly resistant to both beta-lactam antibiotics and fluoroquinolones. Consequently, aminoglycoside antibiotics have undergone a resurgence in use. Because of the known toxicities of aminoglycoside antibiotics, clinicians have avoided their use, unless no other alternatives were extant. Over the past 2 decades, we have learned much about the relationship between aminoglycoside exposure and the likelihood of a good clinical outcome or the occurrence of nephrotoxicity. For example, minimum inhibitory concentration values > or = 2.0 mg/L lead to unacceptably low probabilities of a good clinical outcome, and infrequent administration of doses (i.e., intervals of 24 h and longer intervals for patients with compromised renal function) plays a central role in minimizing the likelihood of toxicity. Using these new insights, we suggest ways of evaluating the dose and schedule of administration of aminoglycosides in empirical therapy to obtain the highest likelihood of an efficacious and nontoxic therapy.


Assuntos
Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/uso terapêutico , Aminoglicosídeos/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Nefropatias/induzido quimicamente , Resultado do Tratamento
13.
Clin Cancer Res ; 12(19): 5770-6, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17020983

RESUMO

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 Prospectivos
15.
Clin Pharmacol Ther ; 79(4): 350-61, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16580903

RESUMO

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 & dosagem
16.
Clin Pharmacol Ther ; 80(5): 531-8, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17112809

RESUMO

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 (P

Assuntos
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
17.
Diagn Microbiol Infect Dis ; 54(4): 267-75, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16466891

RESUMO

The objective of the study were to determine if nationally recognized community-acquired pneumonia (CAP) guidelines (specific to antibiotic therapy) were being followed and to identify outcomes of treatment in hospitals that are VHA members. This was a prospective study using a medication use evaluation in an inpatient setting conducted in 46 institutions in the United States during the 1998-1999 CAP season. The subjects were 875 adult patients (> or =18 years of age) admitted from the emergency department or ambulatory care setting with a chest X-ray-confirmed diagnosis of CAP. Treatment pathways were in place in 58.7% (27/46) of institutions, with 18.3% of patients treated according to pathways. Twenty-seven percent of patients were PSI class I or II. A pathogen (blood or sputum) was identified in <10% of patients. The first dose of antibiotic was administered to patients 65% of the time in the emergency department. Antibiotic therapy in 592 of the 694 admitted to a general medical unit (mortality rate, 3%) complied with 1998 Infectious Diseases Society of America (IDSA) guidelines compared with 26 of the 65 admitted to the intensive care unit (ICU) (mortality rate, 4.6%). In patients admitted to other nongeneral medical, non-ICU areas, IDSA guidelines were followed in 95% of the patients. Mean length of stay and mortality for PSI classes I-V were 4.5, 4.6, 6.9, 6.2, and 7.1 days, respectively, and 0%, 0.7%, 1.1%, 2.5%, and 10.5%, respectively. Antibiotic therapy was modified in 733 of 875 patients. Approximately 90% of patients were eligible for conversion to oral (per os) therapy before discontinuation of parenteral (intravenous) antibiotics (mean time to eligibility, 1.8 days of parenteral antibiotics), with conversion in 65% (mean time to conversion to oral therapy, 4.6 days). Resolution of CAP occurred in 92% of patients; deterioration was more common in PSI class IV and V patients. In conclusion, inhospital mortality rates for all PSI classes were similar to those found in other recently conducted studies despite limited adherence to pathways. Greater use of treatment guidelines for patients admitted to the ICU and awareness of the intravenous to per os antibiotic conversion process are suggested.


Assuntos
Antibacterianos/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/mortalidade , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença , Idoso , Infecções Comunitárias Adquiridas/diagnóstico por imagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/mortalidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Radiografia , Resultado do Tratamento , Estados Unidos
18.
J Clin Pharmacol ; 46(2): 229-34, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16432275

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.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Hipnóticos e Sedativos/sangue , Midazolam/análogos & derivados , Adulto , Algoritmos , Área Sob a Curva , Biotransformação , Humanos , Midazolam/sangue , Estudos Prospectivos , Reprodutibilidade dos Testes
19.
J Clin Pharmacol ; 46(1): 103-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16397289

RESUMO

Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC(0-infinity) 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674-0.765) and 1.392 (1.307-1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC(0-infinity) and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.


Assuntos
Antivirais/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/efeitos dos fármacos , Midazolam/farmacocinética , Oxidiazóis/farmacologia , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Citocromo P-450 CYP3A , Interações Medicamentosas , Feminino , Humanos , Injeções Intravenosas , Fígado/enzimologia , Masculino , Midazolam/administração & dosagem , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacocinética , Oxazóis
20.
J Clin Pharmacol ; 46(3): 345-52, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16490811

RESUMO

To determine the effects of sex and menstrual cycle phase on CYP3A activity and to characterize the intraindividual variability of CYP3A, 24 Caucasian adults were given a single dose of omeprazole every 14th day for 3 months (men) or during the mid-follicular and mid-luteal phases over 3 full menstrual cycles (women). The 2-hour plasma metabolic ratio (MR) (omeprazole/omeprazole sulphone) was used as a measure of CYP3A activity. Overall mean MRs for men (2.4 +/- 1.2) and women (2.3 +/- 0.93) were not significantly different. In women, no difference in mean omeprazole MR was observed between the mid-follicular phase (2.2 +/- 0.85) and mid-luteal phase (2.4 +/- 1.0). When all data in the mid-luteal phase were stratified into 3 groups based on the progesterone concentrations (>50 nM [A], 20-50 nM [B], and <20 nM [C]), the MR of group A was significantly lower than that of B and C. The MRs of women during the mid-luteal phase were weakly correlated with progesterone concentrations (r = -0.35; P = .03). Individual coefficients of variation (CV%) in MR ranged from 8.7% to 60.2%, with a median 30.0%. No sex or menstrual cycle differences in CYP3A activity as measured by the probe drug omeprazole were seen. Higher CYP3A activity in women may be associated with higher endogenous progesterone concentrations.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Omeprazol/análogos & derivados , Omeprazol/farmacologia , Adulto , Biomarcadores/sangue , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/sangue , Feminino , Humanos , Masculino , Ciclo Menstrual/fisiologia , Pessoa de Meia-Idade , Omeprazol/sangue , Progesterona/sangue , Progesterona/metabolismo , Fatores Sexuais , População Branca
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