(T-030) PK/PD/PD Models Enable Quantitative Insights into the Exposure-Efficacy Relationships of Tirzepatide for Treatment of Obstructive Sleep Apnea

Karen Schneck – Eli Lilly and Company; James Tseng – Eli Lilly and Company; Elizabeth LaBell – Eli Lilly and Company; Shweta Urva – Eli Lilly and Company

Objectives: Obstructive sleep apnea (OSA) is marked by interruptions in breathing during sleep due to upper airway blockage [1]. Guidelines advise managing obesity in people with OSA. Tirzepatide is a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist that selectively binds to and activates both the GIP and GLP-1 receptors. Tirzepatide treatment has been associated with reductions in excess body weight and may benefit people with OSA. Data from phase 3 trial SURMOUNT-OSA [2] were evaluated with population pharmacokinetics / pharmacodynamics (PK/PD) models to quantify tirzepatide exposure and efficacy responses.

Methods: The primary efficacy measure was apnea-hypopnea index (AHI), defined as events of apneas and hypopneas per hour of sleep [1]. The PK/PD data included 1013 tirzepatide concentrations, 9186 body weight measurements and 1239 AHI observations over 52 weeks from 458 participants in placebo and tirzepatide arms. Tirzepatide population PK model and population body weight model were previously developed from an extensive trial database. A 2-compartment model with first-order absorption and interindividual variability (IIV) and proportional residual error was used to evaluate tirzepatide concentrations. An indirect response model was used to evaluate tirzepatide effect on body weight. A sequential modeling strategy was used to characterize the effect of tirzepatide on AHI reduction. Post hoc PK/PD parameters were used to predict longitudinal tirzepatide concentrations and body weight reductions. The impact of body weight reduction on PK over time was executed by updating PK with observed weight over time. Weight gains were set in the model to have a neutral effect on baseline AHI. Parameters for fixed effects, IIV, and residual error were estimated using first-order conditional estimation with interaction in the nonlinear mixed effects software NONMEM (v7.5).

Results: PK and exposure in people with OSA and obesity were consistent with the understanding of tirzepatide. No dose adjustments are needed based on body weight, age, sex, race, renal or hepatic impairment, CPAP device use, or ADA presence. The time course and magnitude of body weight reduction with tirzepatide was consistent with outcomes of other phase 3 trials.
The AHI model was a direct exponential relationship between change in body weight (%) and AHI reduction. Females had a 35% lower baseline AHI than males. The model predicted a 50% improvement from baseline AHI with a 11.5% body weight reduction. Visual prediction checks showed good agreement between observed and predicted PK, body weight, and AHI. Simulations showed at least a 50% improvement in AHI with weekly tirzepatide 5 mg, 10mg, and 15 mg after 52 weeks in virtual populations with varying OSA severity.

Conclusions: PK/PD models have quantified the relationships between steady-state exposure of tirzepatide 5 mg, 10 mg, and 15 mg, body weight reduction, and improvement in AHI. These findings support the use of tirzepatide as a treatment option for individuals with OSA and obesity.

Citations: [1] Gottlieb DJ, Punjabi NM. Diagnosis and management of obstructive sleep apnea: a review. JAMA. 2020;323(14):1389-1400.
[2] Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024 Oct 3;391(13):1193-1205.

Keywords: exposure, efficacy, PK/PD