PBPK-Based Prediction of Oliceridine Exposure in Breast Milk and Relative Infant Dose During the First 24 h After...

Oliceridine is an intravenous opioid analgesic for postoperative pain control, but data on transfer into human milk and infant exposure during early breastfeeding remain limited. This study used a postpartum physiologically based pharmacokinetic (PBPK) framework to estimate oliceridine milk exposure and relative infant dose (RID) on postoperative Day 1 (0-24 h) after cesarean delivery under a reconstructed patient-controlled intravenous analgesia regimen. Maternal plasma exposure was simulated in PK-Sim; milk exposure was extrapolated using an externally specified milk-to-plasma ratio (M/P). RID was calculated from mean milk concentration, infant milk intake, and the maternal weight-normalized daily dose. An exposure scaling factor from an independent adult intravenous reference scenario was applied only as a post hoc proportional correction to RID. Morphine benchmarking assessed the physiological plausibility of the M/P extrapolation step, and a 4-24 h temporal sensitivity check examined the influence of the initial accumulation phase. In the base case, maternal plasma AUC over 0-24 h was 120.59 ng·h/mL; mean plasma and milk concentrations were both 5.025 ng/mL. The uncorrected model-predicted RID was 0.375%, and the ESF-corrected RID was 0.307%, both below the empirical 10% reference threshold. In one-way sensitivity analysis, M/P and infant milk intake had greater effects on corrected RID than maternal body weight within the prespecified ranges. The maximum corrected RID was 0.818% in the two-way scan and 1.235% under the prespecified high-exposure scenario. These findings provide a preliminary, assumption-bounded quantitative reference for modeled relative infant exposure under prespecified postoperative Day 1 extrapolation assumptions.