Intranasal Naloxone During Recurrent Exercise in Individuals with Type‐1 Diabetes Mellitus: Evaluation of the Clinical Predictors of Pharmacokinetics and Exposure–Response

Impaired awareness of hypoglycemia (IAH) impacts 25%‐30% of individuals with type 1 diabetes mellitus (T1D), potentially leading to severe outcomes due to reduced symptom perception. Naloxone, a mu‐opioid receptor antagonist, shows promise as a preventive measure against IAH. This study explored intranasal (IN) naloxone as a potential therapy to preserve counterregulatory and symptom responses to hypoglycemia following exercise in T1D patients. Participants included adults with T1D for 2‐20 years. The study aimed to develop a population pharmacokinetic (PopPK) model of IN naloxone and assess exposure–response relationships. The study was conducted as a single‐center, single‐blinded, placebo‐controlled crossover study. It involved collecting blood samples at 12 intervals before, during, and after exercise. Plasma naloxone concentrations were analyzed using high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS). Utilizing nonlinear mixed effects modeling, the PopPK model simulated individual naloxone maximum concentrations (C max ) and total area under the curve (AUC) to evaluate exposure–response relationships. A two‐compartment model with combined zero‐ and first‐order absorption best described the naloxone's pharmacokinetics. Allometric scaling based on weight was applied to volume and clearance parameters, with a combined additive and proportional error model describing residual unexplained variability. Clearance and volume estimates were: central: 6.82 L/min/70 kg and 171 L/70 kg, peripheral: 2.97 L/h/70 kg and 278 L/70 kg. The absorption rate constant and zero‐order absorption duration were 0.0272 min −1 and 7.33 min, respectively. While a strong correlation was observed between simulated exposures (C max and AUC), no statistically significant correlation was found between exposures and responses. This is the first PopPK model of IN naloxone in T1D offering insights for future clinical pharmacokinetic studies.