1 Introduction individual factors due to the heterogeneity of clinical effects. Notably, a recent observational study involving over 1,300 patients highlighted that factors such as male sex, older age, opioid naivety, sleep-disordered breathing, and heart failure are associated with an increased risk of opioid-induced respiratory depression.7 Additional risk factors encompass the presence of comorbidities, concomitant use of systemic opioids and sedatives, and higher BMI.8,9 While clinical trials, typically conducted on young and healthy subjects, illuminate drug effects, questions are raised about the applicability of their findings. Therefore, we focus on studying a new opioid in a representative study sample comprising male and female volunteers of older age, including overweight participants. Of particular interest is the role of obesity as a risk factor for opioid-induced respiratory depression. Obesity’s global prevalence is staggering, and it directly heightens the risk of opioid-induced respiratory depression due to obesity-related changes in the respiratory system, alterations in respiratory drive, and breathing abnormalities during sleep.9,10 Furthermore, obesity increases the likelihood of developing insulin resistance and type 2 diabetes. Intriguingly, studies indicates that insulin resistance can modulate ventilatory drive, and type 2 diabetes can lead to the development of sleep-disordered breathing, independent of obesity.11,12,13 While speculative, these factors may contribute to an elevated risk of premature mortality among individuals with type 2 diabetes who use opioids over an extended period.14 In this thesis, I will present a series of studies conducted in our laboratory, focusing on the pharmacology of ketamine oral and buccal thin film, intravenous oliceridine and morphine, and type 2 diabetes. The studies encompass pharmacological aspects (ketamine, oliceridine, and morphine) and their effects on ventilatory control (morphine, oliceridine, and type 2 diabetes), spanning the important effects of these drugs in clinical practice. Thesis overview While ketamine has been used for nearly six decades, ongoing developments have led to new indications and new formulations are still being developed. As an analgesic, ketamine is employed in the prehospital setting, emergency ward, perioperatively, and for chronic pain syndromes.15,16,17,18 Substantial gaps persist in our understanding of its efficacy and safety when considering different routes of administration, varied durations, dosages, and distinct enantiomers in diverse clinical contexts. This thesis delves into the pharmacology of a novel S-ketamine oral and buccal thin film in Chapters 2 and 3, exploring its pharmacokinetics and pharmacodynamics, respectively. To achieve this, we employ a population pharmacokinetic/pharmacodynamic model, which integrates the changes in 3
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