0641 Population Pharmacokinetic and Exposure-Response Analyses Supporting Individualized Dosing of Oxybate

Abstract Introduction Low-sodium oxybate (LXB; Xywav®) and high-sodium oxybate (SXB; Xyrem®) are approved for the treatment of cataplexy or excessive daytime sleepiness in patients aged ≥7 years with narcolepsy; LXB is also approved for idiopathic hypersomnia in adults. LXB and SXB dosing are individually titrated for optimal efficacy/tolerability. To inform dosing individualization, population pharmacokinetic (PPK) and exposure-response (ER) analyses were conducted to identify factors influencing oxybate PK variability and assess relationships between exposure and efficacy/safety. Methods For narcolepsy, a 2-compartment PPK model with Michaelis-Menten clearance was fit to plasma concentration-time data from prior LXB and SXB clinical studies. For idiopathic hypersomnia, an LXB PPK model was refined based on the narcolepsy model. The PPK model-derived oxybate exposures (eg, AUC) were employed in ER analyses using response data from randomized parallel-group (RPG; SXB only; maintenance dose was not optimized) and randomized withdrawal (RWD; LXB and SXB; maintenance dose was optimized) studies. Results In the narcolepsy PPK model, the interindividual variabilities associated with key clearance and absorption parameters were 42.9%–83.8%, and in the idiopathic hypersomnia PPK model, the interindividual variabilities were 52.7%–57.9%. In both PPK models, food delayed oxybate absorption; greater body weight was associated with wider distribution and higher clearance. In ER analyses from RPG narcolepsy studies, all efficacy endpoints (eg, placebo- and baseline-corrected cataplexy frequency and Epworth Sleepiness Scale ESS score) exhibited improvements (ie, decreases) that had a significant relationship with higher oxybate exposure (AUC); no other covariates (eg, age, race, sex, body weight) were significant. In RWD studies, ER relationships for cataplexy change (narcolepsy only) and ESS score (narcolepsy and idiopathic hypersomnia) were flat, indicating that there is a range of effective concentrations and that different patients require different doses to achieve an optimal response. Adverse events associated with oxybate exposure included nausea, vomiting, and enuresis. Conclusion PPK analyses identified substantial interpatient variability of oxybate PK, and ER analyses demonstrated interindividual variability in response to oxybate treatment. Together, these modeling analyses highlight the need for individually optimized oxybate dosing in narcolepsy or idiopathic hypersomnia to achieve the appropriate dose and associated exposure for an optimal clinical response. Support (if any) Jazz Pharmaceuticals