Too many will quit permanently because they are fed up. Their ambition and self-respect will take them into business or other professions.. .. They leave behind an increasing proportion of tired time-servers.-Life, 16 November 1962 B Y THE FALL of 2000, it had been about a year since we'd started noticing that our master's degree students-conscientious elementary and secondary school teachers-were complaining with increasing bitterness about a changing work environment in the public schools. "The love I had for my work is gone," we were hearing them say. "I never used to feel this way, but now it's hard to drag myself to school each day." Week after week the topic would come up in classes: for many

Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.

AimsRamucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor‐2 (VEGFR‐2) and blocks binding of VEGF‐A, VEGF‐C and VEGF‐D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach.MethodsA total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg−1 every 2 weeks or 10 mg kg−1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics.ResultsThe pharmacokinetics of ramucirumab were well characterized by a two‐compartment model. Mean population estimates of clearance, volume of distribution and half‐life for a typical 68‐kg patient were 0.0148 l h−1, 5.30 l and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; clearance and central compartment volume increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population.ConclusionsThe final model adequately described the concentration–time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight‐normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.

AimsThe effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. MethodsTwenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentrationtime data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day -1 , 30 mg day -1 , or 40 mg day -1 in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day -1 , 40 mg day -1 , or 80 mg day -1 in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling prog ram (NONMEM). ResultsIn Study 1, the elderly ( ≥ 65 years) exhibited a statistically significant slower elimination rate constant l z compared with younger subjects {elderly-younger difference = -0.022 h -1 [95% confidence interval (CI) -0.036, -0.008]}. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h -1 (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies. ConclusionsWhereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower l z in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted. Effect of age on the pharmacokinetics of duloxetine in womenBr J Clin Pharmacol 57 :1 55

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Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Bamlanivimab and etesevimab are potent neutralizing antibodies that target the spike protein of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). WHAT QUESTION DID THIS STUDY ADDRESS? This study characterizes the pharmacokinetics (PKs) of bamlanivimab and etesevimab and the exposure-response relationship for reduction in viral load in patients with coronavirus disease 2019 (COVID-19). The study identified the optimal doses and investigated the impact of various demographic factors that could affect therapeutic response to the neutralizing antibodies.

An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure-response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017).

Purpose We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. Methods The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. Results Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. Conclusion Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.