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Biomedical subjects

Howard Lee

Publications and source records attributed to Howard Lee.

11 recordsLinked to original sources
PubMed2006

Aspiration rate following nonsurgical therapy for laryngeal cancer.

The aim of this study was to evaluate the aspiration rate following nonsurgical therapy, i.e. chemoradiation or radiation alone for laryngeal cancer. Modified barium swallow was performed in 43 patients who complained of dysphagia following chemoradiation (n = 22) or radiation alone (n = 21) for laryngeal cancer. Patients were selected if they were cancer free at the time of the swallowing study. Dysphagia severity was graded on a scale of 1-7. Patients were grouped according to the dysphagia severity: no aspiration (grade 1-4), and severe (grade 5-7). Mean and median dysphagia grades were 4.4/5 and 3.5/3 for chemoradiation and radiation, respectively. Aspiration occurred in 12 patients (54%) of the chemoradiation group and 7 (33%) of the radiation alone group (p = 0.13). There was a higher proportion of patients with large tumor (T3-T4) in the chemoradiation group (64%) compared to the radiation group (5%) (p = 0.0001). Aspiration is a significant source of morbidity in patients treated for laryngeal cancer with chemoradiation or radiation alone. Aspiration occurred in both groups. Although the observed difference in aspiration rates did not achieve statistical significance, the higher aspiration rate in the chemoradiation group may be due to a higher proportion of large tumors, to the additional toxic effect of chemotherapy, or to the small number of patients in both groups. Diagnostic studies such as modified barium swallow should be part of future laryngeal cancer prospective studies to assess the prevalence of aspiration as it may be silent.

Aged↗
PubMed2006

Simulation of correlated continuous and categorical variables using a single multivariate distribution.

Clinical trial simulations make use of input/output models with covariate effects; the virtual patient population generated for the simulation should therefore display physiologically reasonable covariate distributions. Covariate distribution modeling is one method used to create sets of covariate values (vectors) that characterize individual virtual patients, which should be representative of real subjects participating in clinical trials. Covariates can be continuous (e.g., body weight, age) or categorical (e.g., sex, race). A modeling method commonly used for incorporating both continuous and categorical covariates, the Discrete method, requires the patient population to be divided into subgroups for each unique combination of categorical covariates, with separate multivariate functions for the continuous covariates in each subset. However, when there are multiple categorical covariates this approach can result in subgroups with very few representative patients, and thus, insufficient data to build a model that characterizes these patient groups. To resolve this limitation, an application of a statistical methodology (Continuous method) was conceived to enable sampling of complete covariate vectors, including both continuous and categorical covariates, from a single multivariate function. The Discrete and Continuous methods were compared using both simulated and real data with respect to their ability to generate virtual patient distributions that match a target population. The simulated data sets consisted of one categorical and two correlated continuous covariates. The proportion of patients in each subgroup, correlation between the continuous covariates, and ratio of the means of the continuous covariates in the subgroups were varied. During evaluation, both methods accurately generated the summary statistics and proper proportions of the target population. In general, the Continuous method performed as well as the Discrete method, except when the subgroups, defined by categorical value, had markedly different continuous covariate means, for which, in the authors' experience, there are few clinically relevant examples. The Continuous method allows analysis of the full population instead of multiple subgroups, reducing the number of analyses that must be performed, and thereby increasing efficiency. More importantly, analyzing a larger pool of data increases the precision of the covariance estimates of the covariates, thus improving the accuracy of the description of the covariate distribution in the simulated population.

Clinical Trials as Topic↗
PubMed2005

The link between obesity and the built environment. Evidence from an ecological analysis of obesity and vehicle miles of travel in California.

AIMS: Obesity and physical inactivity are known to be risk factors for many chronic diseases including hypertension, coronary artery disease, diabetes, and cancer. We sought to explore the association between an indicator of transportation data (Vehicle Miles of Travel, VMT) at the county level as it relates to obesity and physical inactivity in California. METHODS: Data from the California Health Interview Survey 2001 (CHIS 2001), the US 2000 Census, and the California Department of Transportation were merged to examine ecological correlations between vehicle miles of travel, population density, commute time, and county indicators of obesity and physical inactivity. Obesity was measured by body mass index (BMI). Physical inactivity was based on self-reported behaviors including walking, bicycling, and moderate to vigorous activity. The unit of analysis was the county. Thirty-three counties in California with population size greater than 100,000 persons per county were retained in the analyses. RESULTS: CHIS 2001 statewide obesity prevalence ranged from 11.2% to 28.5% by county. Physical inactivity ranged from 13.4% to 35.7%. Daily vehicle miles of travel ranged from 3.3 million to 183.8 million per county. By rank bivariate correlation, obesity and physical inactivity were significantly associated (p<0.01). Furthermore, by rank analysis of variance, the highest mean rank obesity was associated with the highest rank of VMT (p<0.01). Similar rank patterns were observed between obesity and physical inactivity and commute time. Associations between VMT and physical inactivity were examined but failed to reach statistical significance. CONCLUSION: This analysis adds to the growing evidence supporting the association between VMT (a measure of automobile transportation) and obesity. An urban design characterized by over dependence on motorized transportation may be related to adverse health effects.

Adolescent↗
PubMed2005

Evidence of effectiveness: how much can we extrapolate from existing studies?

Drug development can be a science of extrapolation if the use of a drug exposure-response relationship is embraced and implemented through mechanistically oriented pharmacokinetic (PK)-pharmacodynamic (PD) modeling analysis and clinical trial simulation. The traditional requirement of at least 2 adequate and well-controlled phase III studies by the US Food and Drug Administration for drug approval can be waived in certain situations, substantially reducing the resources and time. In this article, the authors introduce a real drug development case where the chance for this exemption was maximized by actively using PK-PD modeling followed by clinical trial simulation, resulting in faster and more economical introduction of a new dosage regimen to patients.

Animals↗
PubMed2005

Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis.

This study was performed to estimate the population pharmacokinetic (PK) parameters of etanercept in pediatric juvenile rheumatoid arthritis (JRA) patients and to compare the steady-state time-concentration profiles between etanercept 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly subcutaneous (SC) regimens by clinical trial simulation. To this end, mixed-effect analysis (NONMEM, Version 5.1) was performed using the etanercept PK database consisting of 69 JRA patients (4-17 years). Based on the population PK parameters obtained herein, a Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles in 200 virtual JRA patients who randomly received either etanercept 0.4 mg/kg SC twice weekly or 0.8 mg/kg once weekly for 12 weeks. The following population PK model could adequately describe etanercept PK profiles for twice-weekly SC dosing of 0.4 mg/kg: CL/F (L/h)=0.0576 (female) or 0.0772 (male) x (body surface area in m2/1.071)1.41, V/F(L)=7.88 x (body weight in kg/30.8). The means +/- standard deviations of simulated trough concentrations for 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly dosing regimens were 1.58 +/- 1.07 mg/L and 1.92 +/- 1.09 mg/L, respectively. Peaks during 0.8-mg/kg once-weekly dosing (2.92 +/- 1.41 mg/L) were only 11% higher than during 0.4 mg/kg twice-weekly dosing (2.62 +/- 1.23 mg/L). In conclusion, the clinical trial simulation confirmed that 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly SC regimens of etanercept are expected to yield overlapping steady-state time-concentration profiles, leading to equivalent clinical outcomes. This has been the basis of the recent Food and Drug Administration approval of the 0.8-mg/kg once-weekly regimen in pediatric patients with JRA.

Adolescent↗
PubMed2005

Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy.

OBJECTIVE: Cancer-related anaemia is associated with fatigue that adversely affects patients' everyday functioning and wellbeing. We explore the impact of fatigue on patient productivity and caregiver burden. METHODS: The analyses are based on data from a randomised, open-label, active-controlled, dose-finding trial of darbepoetin alfa among solid-tumour cancer patients with anaemia, who are receiving chemotherapy. Fatigue is assessed with the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale score. Productivity and caregiver outcomes include time (hours) missed from usual activities, amount of assistance (hours) needed from others, overall ability to perform desired activities and ability to perform family responsibilities. These outcomes are assessed at baseline and the end of the 12-week treatment period. ANOVA and linear regression models are used to evaluate associations. RESULTS: Patients (n=300) were aged 61 years on average, with a mean (SD) baseline haemoglobin of 9.9 (0.9) g/dL. FACT-Fatigue subscale score improvements were significantly (p=0.003) associated with haemoglobin improvements. Over a 2-week period, after controlling for age, sex and disease progression, one-point improvements in FACT-Fatigue subscale scores corresponded to a 1-hour (95% CI 0.5, 1.5) gain in productive time, 0.7-hour (95% CI 0.4, 1.0) reduction in caregiver time and 1.6% (95% CI 1.4, 1.7) improvement in overall activity. CONCLUSIONS: Reducing fatigue is associated with gains in productive time, reductions in caregiver burden and enhanced ability to perform activities. These outcomes may have broader implications for patients' wellbeing and for the societal impact of cancer-related fatigue and anaemia.

Adult↗
PubMed2003

The impact of frequent injections for hematopoietic growth factor support on patients receiving chemotherapy: an observational study.

BACKGROUND: Quality of life may be affected by daily injections of supportive hematopoietic growth factor medication, which is frequently required by patients with cancer undergoing chemotherapy. The objective of the study was to identify areas where long-acting derivatives of current proteins, which require less frequent administration, may provide advantages over existing therapies that require more frequent administration. METHODS: An observational study was conducted to assess the impact of daily injections of Filgrastim (NeupogencircledR;; Amgen Inc.) on patients' quality of life. A Subject Outcome Questionnaire was administered to patients after chemotherapy on 2 consecutive cycles. Time spent for treatment and patient attitude towards injection frequency were measured. The effect on patients' daily activities, including their ability to work, was analyzed. RESULTS: Thirty patients completed the first, and 24 the second, administration of the Questionnaire across 3 participating sites in the United States. The average patient time commitment for each daily injection was 78 minutes. Forty-five percent of patients were moderately to extremely bothered by travel during the first chemotherapy cycle, which increased to 59% during the second cycle. Forty-four percent and 18% of patients reported having to rearrange their daily schedules and take time off from work to accommodate each injection at least some of the time, respectively. Eighty-nine percent of the patients reported a preference for a longer-acting drug that required fewer injections. CONCLUSION: Results indicate that frequent injections represent a significant burden on patients' lives and that the majority would prefer longer-acting medications that require less frequent administration and potentially fewer clinic visits.

Journal Article↗
PubMed2003

Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis.

OBJECTIVE: Our objective was to develop a population pharmacokinetic and pharmacodynamic model of etanercept in patients with rheumatoid arthritis, with the American College of Rheumatology response criterion of 20% improvement (ACR20) used as a binary clinical outcome variable. METHODS: Concentration-time profiles from 25 subjects, administered 25 mg subcutaneous etanercept twice weekly for 24 weeks, were pooled with data from 77 subjects, enrolled in a 24-week, randomized, double-blind study comparing 25 mg and 50 mg subcutaneous etanercept twice weekly. The cumulative area under the concentration-time curve (AUC) was used as the exposure variable, and ACR20 was the binomial clinical outcome. ACR20 data from another 80 placebo-treated patients enrolled in a randomized, double-blind phase III study were used to describe the placebo time course of ACR20. A logistic regression analysis with NONMEM was applied to describe the exposure-response relationship, and the 95% confidence intervals (95% CIs) were constructed by bootstrapping 1000 times. RESULTS: The population mean apparent clearance was 0.117 L/h (95% CI, 0.108-0.130 L/h) for white female patients and 0.138 L/h (95% CI, 0.118-0.163 L/h) for white male patients. Interindividual variability and interoccasion variability were 41.1% and 27.6%, respectively. The mean absorption half-life was 20.9 hours, and the elimination half-life was 95.4 hours. An improved response profile in male patients was shown, but the multiplicative factor between slope on cumulative AUC between male and female patients was not statistically significant (1.69; 95% CI, 0.37-9.99). The model-predicted percentage of patients achieving ACR20 at 6 months after dosing of 25 mg subcutaneously twice weekly was 54.9%, comparable to the observed 52.9%. CONCLUSION: The population pharmacokinetic analysis confirmed that etanercept is slowly absorbed and eliminated after subcutaneous administration. The logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in patients with rheumatoid arthritis receiving etanercept.

Area Under Curve↗
PubMed2002

Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999.

PURPOSE: Risks and benefits of marketed drugs can be improved by changing their labels to optimize dosage regimens for indicated populations. Such postmarketing label changes may reflect the quality of pre-marketing development, regulatory review, and postmarketing surveillance. We documented dosage changes of FDA-approved new molecular entities (NMEs), and investigated trends over time and across therapeutic groups, on the premise that improved drug development methods have yielded fewer postmarketing label changes over time. METHODS: We compiled a list of NMEs approved by FDA from 1 January 1980 to 31 December 1999 using FDA's website, Freedom of Information Act request, and PhRMA (Pharmaceutical Research and Manufacturers of America) database. Original labeled dosages and indicated patient populations were tracked in labels in the Physician's Desk Reference. Time and covariate-adjusted risks for dosage changes by 5-year epoch and therapeutic groups were estimated by survival analysis. RESULTS: Of 499 NMEs, 354 (71%) were evaluable. Dosage changes in indicated populations occurred in 73 NMEs (21%). A total of 58 (79%) were safety-motivated, net dosage decreases. Percentage of NMEs with changes by therapeutic group ranged from 27.3% for neuropharmacologic drugs to 13.6% for miscellaneous drugs. Median time to change following approval fell from 6.5 years (1980-1984) to 2.0 years (1995-1999). Contrary to our premise, 1995-1999 NMEs were 3.15 times more likely to change in comparison to 1980-1984 NMEs (p = 0.008, Cox analysis). CONCLUSIONS: Dosages of one in five NMEs changed, four in five changes were safety reductions. Increasing frequency of changes, independent of therapeutic group, may reflect intensified postmarketing surveillance and underscores the need to improve pre-marketing optimization of dosage and indicated population.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

The economic burden of anemia in cancer patients receiving chemotherapy.

BACKGROUND: Anemia is one of the most common hematologic complications of cancer and cytotoxic treatment. The economic burden associated with anemia in patients with malignancy has not yet been extensively studied. METHODS: Patients receiving chemotherapy within 6 months of initial cancer diagnosis were identified in a database of commercial health-care service claims and encounters. Patients with anemia were identified through a coded diagnosis of anemia, transfusion, or erythropoietin treatment. Exponential conditional mean models and a decomposition analysis were used to analyze mean 6-month health-care expenditures. RESULTS: Twenty-six percent (26%) of 2760 cancer patients with recently diagnosed invasive cancer treated with chemotherapy had anemia. Mean (SD) 6-month unadjusted total expenditures were 62,499 dollars (78,016 dollars) for anemic patients and 36,871 dollars (52,308 dollars) for nonanemic patients (P < 0.0001), with inpatient services representing the largest cost differential between the groups. The adjusted mean 6-month expenditure for the average anemic patient receiving chemotherapy was 57,209 dollars. If anemic patients had the same average health status as nonanemic patients, their predicted 6-month expenditures would have been 19% lower (46,237 dollars). Alternatively, if anemic patients had the same expenditure structure or parameter estimates as nonanemic patients, their predicted expenditures would have been 51% lower (27,847 dollars). Thus, for any given health status, treating a patient who is anemic is associated with considerably higher expenditures. CONCLUSIONS: Anemia among cancer patients receiving chemotherapy is associated with a substantial burden in terms of direct medical costs. Implications for the treatment of anemia are suggested by this research and should be confirmed in prospective studies.

Aged↗