Bioavailability of Cadmium in Inexpensive Jewelry

Objectives: We evaluated the bioavailability of Cd in 86 components of 57 jewelry items found to contain high levels of Cd (> 10,000 ppm) by X-ray fluorescence (XRF), using extractions that simulate mouthing or swallowing of jewelry items

Efficiency of a randomized confirmatory basket trial design constrained to control the family wise error rate by indication

Basket trials pool histologic indications sharing molecular pathophysiology, improving development efficiency. Currently basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power even with modest effect sizes, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since family-wise error rate by indications (FWER) may sometimes be required, we now simulate a variant of this basket design controlling FWER at 0.025k, the total FWER of k separate randomized trials. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling FWER and minimizing estimation bias were allowable. Optimal performance results when k=3,4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power (“uncorrected”) or at the power achieved in the basket trial (“corrected”, because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible. Even under FWER control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical

Evaluation of time-dependent toxicity and combined effects for a series of mono-halogenated acetonitrile-containing binary mixtures

Mixture and time-dependent toxicity (TDT) was assessed for a series of mono-halogenated acetonitrile-containing combinations. Inhibition of bioluminescence in Aliivibrio fischeri was measured after 15, 30 and 45-min of exposure. Concentration-response (x/y) curves were determined for each chemical alone at each timepoint, and used to develop predicted x/y curves for the dose-addition and independence models of combined effect. The x/y data for each binary mixture was then evaluated against the predicted mixture curves. Two metrics of mixture toxicity were calculated per combined effect model: (1) an EC50-based dose-addition (AQ) or independence (IQ) quotient and (2) the mixture/dose-addition (MX/DA) and mixture/independence (MX/I) metrics. For each single chemical and mixture tested, TDT was also calculated. After 45-min of exposure, 25 of 67 mixtures produced curves that were consistent with dose-addition using the MX/DA metric, with the other 42 being less toxic than predicted by MX/DA. Some mixtures had toxicity that was consistent with both dose-addition and independence. In general, those that were less toxic than predicted for dose-addition were also less toxic than predicted for independence. Of the 25 combinations that were consistent with dose-addition, 22 (88%) mixtures contained chemicals for which the individual TDT values were both >80%. In contrast, of the 42 non-dose-additive combinations, only 2 (4.8%) of the mixtures had both chemicals with individual TDT values >80%. The results support previous findings that TDT determinations can be useful for predicting chemical mixture toxicity. Keywords: Microtox®, Acute toxicity, Dose-addition, Independenc

Roadmap to 2030 for Drug Evaluation in Older Adults

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults