The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug's stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are unacceptable variation in the bioavailability and high investment costs. Furthermore, novel oral anticancer drugs are frequently associated with toxic effects including unacceptable gastrointestinal adverse effects. Therefore, compliance is often suboptimal, which may negatively influence treatment outcome.

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Significance Statement--Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.

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Background Diagnosis and follow‐up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel. Smartphone‐connected spirometers, like the Air Next spirometer, have been developed to aid in the home monitoring of patients with pulmonary disease. The aim of this study was to investigate the technical validity and usability of the Air Next spirometer in pediatric patients. Methods Device variability was tested with a calibrated syringe. About 90 subjects, aged 6 to 16, were included in a prospective cohort study. Fifty‐eight subjects performed conventional spirometry and subsequent Air Next spirometry. The bias and the limits of agreement between the measurements were calculated. Furthermore, subjects used the device for 28 days at home and completed a subject‐satisfaction questionnaire at the end of the study period. Results Interdevice variability was 2.8% and intradevice variability was 0.9%. The average difference between the Air Next and conventional spirometry was 40 mL for forced expiratory volume in 1 second (FEV1) and 3 mL for forced vital capacity (FVC). The limits of agreement were −270 mL and +352 mL for FEV1 and −403 mL and +397 mL for FVC. About 45% of FEV1 measurements and 41% of FVC measurements at home were acceptable and reproducible according to American Thoracic Society/European Respiratory Society criteria. Parents scored difficulty, usefulness, and reliability of the device 1.9, 3.5, and 3.8 out of 5, respectively. Conclusion The Air Next device shows validity for the measurement of FEV1 and FVC in a pediatric patient population.

Background Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children. Methods Apparently healthy children (n = 175, 46% male) aged 2–16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated. Findings Median compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33–110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature. Conclusions Wearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures.