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Sepsis is defined as a dysregulated host response to infection, and high‐dose melatonin has been proposed as a treatment due to its antioxidant and anti‐inflammatory properties. However, there are no data describing the pharmacokinetics of high‐dose oral melatonin in critically ill patients. We undertook an open‐label trial to determine the tolerance of melatonin administration in these patients and pharmacokinetic analysis, to inform a planned randomised controlled trial. Two cohorts of critically ill patients with sepsis due to community‐acquired pneumonia received either 20 or 50 mg oral melatonin liquid as a single dose. Blood samples and clinical measures were analysed over the next 24 h. Melatonin was well tolerated and there were no adverse events. Pharmacokinetic modelling showed that a semiphysiological model, which incorporates saturable first‐pass hepatic extraction, was a good fit for our data. Maximum levels of melatonin were extremely high in patients receiving the 50 mg dose and levels of the major metabolite were much lower than expected and not different from those seen after 20 mg, suggesting saturation at the higher dose. We conclude that 20 mg seems a suitable dose of liquid melatonin in patients with sepsis. [ABSTRACT FROM AUTHOR]

This paper demonstrates the use of a genetic algorithm (GA) for the optimization of a dosing guideline. GAs are well‐suited to derive combinations of doses and dosing intervals that go into a dosing guideline when the number of possible combinations rule out the calculation of all possible outcomes. GAs also allow for different constraints to be imposed on the optimization process to safeguard the clinical feasibility of the dosing guideline. In this work, we demonstrate the use of a GA for the optimization of intermittent vancomycin administration in adult patients. Constraints were placed on the dose strengths, the length of the dosing intervals, and the maximum infusion rate. In addition, flexibility with respect to the timing of the first maintenance dose was included in the optimization process. The GA‐based optimal solution is compared with the Scottish Antimicrobial Prescribing Group vancomycin guideline. [ABSTRACT FROM AUTHOR]

This article discusses the need for improved labeling recommendations for medications used during pregnancy and breastfeeding. Currently, there is a lack of data on the safety and efficacy of drugs for these populations, as they are often excluded from drug development programs. The article highlights the value of Model Informed Drug Development (MIDD) in generating data and improving accessibility to safe and effective medicines. Regulatory developments and advancements in nonclinical drug development methodologies and MIDD are expected to enhance the safe use of medicines during pregnancy and breastfeeding. However, challenges remain, including limited experience with MIDD in this context and the uncertainty associated with model predictions. Efforts are being made to improve knowledge through data collection and the development of new methods. European regulators are open to discussions to improve labeling for medicines used during pregnancy and breastfeeding. [Extracted from the article]