Effect of obesity on pharmacokinetics and drug dosing of remimazolam in patients with obstructive sleep apnoea

INTRODUCTION: The pharmacological profile of remimazolam makes it particularly suitable for patients living with obesity. However, how its pharmacokinetics are influenced by varying degrees of obesity and obstructive sleep apnoea severity remains unclear. This study aimed to characterise remimazolam pharmacokinetics in volunteers living with different levels of obesity and obstructive sleep apnoea. METHODS: Stepwise escalating infusion of remimazolam was administered until five consecutive modified observer's assessment of alertness and sedation scores of 1 were recorded. Arterial blood samples were collected before infusion, at each infusion rate adjustment step, 5 minutes after each adjustment and several time points post-infusion discontinuation. Drug concentrations were quantified using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. A joint population pharmacokinetic model characterising remimazolam and its metabolite CNS7054 was developed. Total body weight significantly affected clearance and metabolite volume of distribution. No other covariates, including obstructive sleep apnoea severity, had significant impact. In patients living with class 2/3 obesity, context-sensitive half-time after a 4-h infusion was short (4.02 min). Dosing based on lean/ideal body weight for induction, or adjusted body weight for maintenance, in patients living with class 2/3 obesity yielded pharmacokinetic profiles comparable with those achieved with total body weight dosing in normal weight patients. DISCUSSION: Body size significantly alters remimazolam pharmacokinetics and individualised weight-based dosing is essential for populations with obesity. Obstructive sleep apnoea severity does not affect drug disposition; however, its pharmacodynamic effects require further investigation.