Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the children's oncology group.

Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed-effects modeling with the NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites

A Guide to Handling Missing Data in Cost-Effectiveness Analysis Conducted Within Randomised Controlled Trials

The authors would like to thank Professor Adrian Grant and the team at the University of Aberdeen (Professor Craig Ramsay, Janice Cruden, Charles Boachie, Professor Marion Campbell and Seonaidh Cotton) who kindly allowed the REFLUX dataset to be used for this work, and Eldon Spackman for kindly sharing the Stata (R) code for calculating the probability that an intervention is cost effective following MI. The authors are grateful to the reviewers for their comments, which greatly improved this paper. M. G. is recipient of a Medical Research Council Early Career Fellowship in Economics of Health (grant number: MR/K02177X/1). I. R. W. was supported by the Medical Research Council [Unit Programme U105260558]. No specific funding was obtained to produce this paper. The authors declare no conflicts of interest.Missing data are a frequent problem in cost-effectiveness analysis (CEA) within a randomised controlled trial. Inappropriate methods to handle missing data can lead to misleading results and ultimately can affect the decision of whether an intervention is good value for money. This article provides practical guidance on how to handle missing data in within-trial CEAs following a principled approach: (i) the analysis should be based on a plausible assumption for the missing data mechanism, i.e. whether the probability that data are missing is independent of or dependent on the observed and/or unobserved values; (ii) the method chosen for the base-case should fit with the assumed mechanism; and (iii) sensitivity analysis should be conducted to explore to what extent the results change with the assumption made. This approach is implemented in three stages, which are described in detail: (1) descriptive analysis to inform the assumption on the missing data mechanism; (2) how to choose between alternative methods given their underlying assumptions; and (3) methods for sensitivity analysis. The case study illustrates how to apply this approach in practice, including software code. The article concludes with recommendations for practice and suggestions for future research.Medical Research Council Early Career Fellowship in Economics of Health MR/K02177X/1Medical Research Council UK (MRC) U105260558Medical Research Council UK (MRC) MC_U105260558 MR/K02177X/

Scaling matters: incorporating body composition into Weddell seal seasonal oxygen store comparisons reveals maintenance of aerobic capacities

Adult Weddell seals (Leptonychotes weddellii) haul-out on the ice in October/November (austral spring) for the breeding season and reduce foraging activities for ~4 months until their molt in the austral fall (January/February). After these periods, animals are at their leanest and resume actively foraging for the austral winter. In mammals, decreased exercise and hypoxia exposure typically lead to decreased production of O2-carrying proteins and muscle wasting, while endurance training increases aerobic potential. To test whether similar effects were present in marine mammals, this study compared the physiology of 53 post-molt female Weddell seals in the austral fall to 47 pre-breeding females during the spring in McMurdo Sound, Antarctica. Once body mass and condition (lipid) were controlled for, there were no seasonal changes in total body oxygen (TBO2) stores. Within each season, hematocrit and hemoglobin values were negatively correlated with animal size, and larger animals had lower mass-specific TBO2 stores. But because larger seals had lower mass-specific metabolic rates, their calculated aerobic dive limit was similar to smaller seals. Indicators of muscular efficiency, myosin heavy chain composition, myoglobin concentrations, and aerobic enzyme activities (citrate synthase and β-hydroxyacyl CoA dehydrogenase) were likewise maintained across the year. The preservation of aerobic capacity is likely critical to foraging capabilities, so that following the molt Weddell seals can rapidly regain body mass at the start of winter foraging. In contrast, muscle lactate dehydrogenase activity, a marker of anaerobic metabolism, exhibited seasonal plasticity in this diving top predator and was lowest after the summer period of reduced activity

Patient-Level Estimates of the Cost of Complications in Diabetes in a Managed-Care Population

Objective: To develop incidence-based estimates of the cost of several diabetes-related complications. Design and setting: This was a retrospective cohort study in a large health maintenance organisation. A total of 8905 patients with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus and 36 520 age- and gender-matched controls without diabetes were observed from 1992 to 1995. Incidence rates of 6 major diabetes-related complications were computed for both populations. Annual health expenditures in the first and second year following diagnosis were computed for each complication. For comparison, annual costs were derived for individuals without diabetes or the complication of interest. Main outcome measures and results: Over 3 years of observation, incidence rates for the groups with and without diabetes were as follows: myocardial infarction 9.0 versus 3.2%; stroke 8.7 versus 3.8%; hypertension 26.2 versus 16.9%; end-stage renal disease 5.9 versus 1.4%; foot ulcer 7.9 versus 1.1%; and eye disease 44.3 versus 2.8%. Expressed as a multiple of the average annual cost of care for those without diabetes [$US3400/year (1995 dollars) for those over 65 years of age] and the related complication of interest, excess expenditures for those with diabetes were as follows for the first year following diagnosis: no complications 1.59; myocardial infarction 4.1; stroke 3.5; hypertension 2.56; end-stage renal disease 4.32; foot ulcer 4.0; and eye disease 2.46. For younger cohorts (less prevalent in the sample), incremental costs for each complication were generally greater than in the older group. Conclusions: The high incidences and costs may support the value of aggressive early intervention for patients with diabetes. These data will be useful for pharmacoeconomic modelling of the cost effectiveness of new and existing therapies for this condition.Pharmacoeconomics, Cost-analysis, Diabetic-complications, Diabetic-angiopathies, Diabetic-foot, Diabetic-nephropathies, Diabetic-retinopathy, Type-1-diabetes-mellitus, Type-2-diabetes-mellitus, Myocardial-infarction, Essential-hypertension, Renal-failure, Stroke

Is a comparative clinical trial for breast cancer tumor markers to monitor disease recurrence warranted? A value of information analysis

The production of sound, clean fruit is unquestionably one of the major problems facing the modern fruit grower. Culture may be neglected and pruning delayed for a time but the omission of sprays for even a single season demonstrates their absolute necessity. This applies equally to the commercial grower and to the farmer or gardener who has only a few trees

Predicting costs of care in heart failure patients

Abstract Background Identifying heart failure patients most likely to suffer poor outcomes is an essential part of delivering interventions to those most likely to benefit. We sought a comprehensive account of heart failure events and their cumulative economic burden by examining patient characteristics that predict increased cost or poor outcomes. Methods We collected electronic medical data from members of a large HMO who had a heart failure diagnosis and an echocardiogram from 1999–2004, and followed them for one year. We examined the role of demographics, clinical and laboratory findings, comorbid disease and whether the heart failure was incident, as well as mortality. We used regression methods appropriate for censored cost data. Results Of the 4,696 patients, 8% were incident. Several diseases were associated with significantly higher and economically relevant cost changes, including atrial fibrillation (15% higher), coronary artery disease (14% higher), chronic lung disease (29% higher), depression (36% higher), diabetes (38% higher) and hyperlipidemia (21% higher). Some factors were associated with costs in a counterintuitive fashion (i.e. lower costs in the presence of the factor) including age, ejection fraction and anemia. But anemia and ejection fraction were also associated with a higher death rate. Conclusions Close control of factors that are independently associated with higher cost or poor outcomes may be important for disease management. Analysis of costs in a disease like heart failure that has a high death rate underscores the need for economic methods to consider how mortality should best be considered in costing studies.</p

Association of Preexisting Symptoms with Treatment Decisions among Newly Diagnosed Prostate Cancer Patients.

BACKGROUND: The choice between surgical versus non-surgical treatment options is a fundamental decision for men with local stage prostate cancer because of differences in risks of genitourinary side effects among available treatments. OBJECTIVES: We assessed whether preexisting genitourinary symptoms at the time of diagnosis influenced men's preferences for surgery versus other management options. METHODS: We recruited 593 patients with newly diagnosed local stage prostate cancer prior to initiating treatment from an integrated health care system, an academic urology center, and community urology clinics. Using logistic regression we compared whether men had a preference for non-surgical options or only preferred surgery. RESULTS: Nearly 60% indicated they were considering non-surgical options. Age and clinical characteristics but not preexisting genitourinary symptoms influenced the decision between preferences for surgical or non-surgical options. A total of 62% of men reported side effects as a main factor in their treatment decision. Men with more aggressive tumor types were less likely to consider side effects, however, men who reported poor ability to have an erection were more likely to consider side effects (p<0.001). CONCLUSION: Sexual dysfunction at time of diagnosis, but not other genitourinary symptoms, is associated with men considering treatment-related side effects when considering surgery versus other options. Men who are not experiencing sexual dysfunction at diagnosis may discount the risks of side effects in the decision making process

Risk factors for statin-associated rhabdomyolysis

PURPOSE: To identify and characterize risk factors for rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy. METHODS: A nested case-control study was conducted within a cohort of 252,460 new users of lipid-lowering medications across 11 geographically dispersed U.S. health plans. Twenty-one cases of rhabdomyolysis confirmed by medical record review were compared to 200 individually matched controls without rhabdomyolysis. A conditional logistic regression model was applied to evaluate the effects of age, gender, comorbidities, concurrent medication use, dosage, and duration of statin use on the development of rhabdomyolysis. RESULTS: Statin users 65 years of age and older have four times the risk of hospitalization for rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence interval (CI): 1.5,14.1). We also observed a joint effect of high statin dosage and renal disease (p = 0.022). When these two variables were added to the model with age, we obtained an OR of 5.73 for dosage (95%CI: 0.63, 52.6) and 6.26 for renal disease (95%CI: 0.46, 63.38). Although not statistically significant, we did observe a greater than twofold increase in risk for rhabdomyolysis among females (OR = 2.53, 95%CI: 0.91, 7.32). CONCLUSIONS: Findings of this study indicate that older age is a risk factor for rhabdomyolysis among statin users. Although the evidence is not as strong, high statin dosage, renal disease, and female gender may be additional risk factors. Patients at higher risk of developing rhabdomyolysis should be closely monitored for signs and symptoms of the disease