Pharmacokinetic/Pharmacodynamic Manager Heron Therapeutics San Diego, CA
Poster Type: Evaluative Study Category Topic: Pharmacokinetics
Purpose: Local anesthetics can pass from maternal blood into breast milk. HTX-011, an investigational drug, is a dual-acting local anesthetic comprising the active ingredients bupivacaine and low-dose meloxicam in an FDA-approved polymer designed for controlled diffusion of ingredients over 72 hours. Locally applied meloxicam reduces inflammation and normalizes local pH, allowing enhanced penetration of bupivacaine into the nerves and potentiation of its analgesic effect. Here, we present interim results of a study examining the pharmacokinetics (PK) of the active ingredients, and an inactive formulation ingredient, dimethyl sulfoxide (DMSO), of HTX-011 in plasma and breast milk following maternal administration after Cesarean section.
Methods: This ongoing phase 2, open-label study (NCT03955211) enrolled women undergoing a planned Cesarean section who had previously chosen not to breastfeed their newborn. All patients underwent surgery under ropivacaine spinal anesthesia. Following delivery of the neonate and prior to skin closure, HTX-011 (300 mg bupivacaine/9 mg meloxicam) was applied without a needle to the surgical site and surrounding tissues. Samples of maternal blood and complete expression of breast milk were collected through postpartum Day 16. Plasma and breast milk concentrations of bupivacaine, meloxicam, and DMSO were measured using validated liquid chromatography tandem-mass spectrometry assays. PK parameters were calculated using a standard noncompartmental analysis method.
At this interim analysis, 12 women had received HTX-011 and completed the study. Adequate PK samples for breast milk were available from ≥8 women (the number of samples varied between analytes) and for plasma from 11 women.
Results: On average, < 0.1% of the HTX-011 dose was excreted in breast milk with quantifiable levels at microgram concentrations observed for ≤6 days postpartum. Mean total amounts of bupivacaine, meloxicam, and DMSO detected in breast milk were 4.90 µg, 0.924 µg, and 48.3 µg, respectively. Median time to maximum concentration (Tmax) in breast milk was 48 hours for bupivacaine, 60 hours for meloxicam, and 12 hours for DMSO. Extrapolating these data to an HTX-011 dose of 400 mg/12 mg (studied in an additional cohort) would be expected to lead to a 33% higher concentration of these components in breast milk. No toxicity was observed in neonatal pigs administered bupivacaine 0.25 mg/kg/day, meloxicam 12 mg/kg/day, and DMSO 80 mg/kg/day (≈237-, 48,600-, and 3500-times greater, respectively, than the maximum daily infant dose from breast milk based on body surface area).
Mean maximum plasma concentration (Cmax) was 235 ng/mL for bupivacaine and 75.9 ng/mL for meloxicam. Mean Cmax of DMSO was 3690 ng/mL. Median plasma Tmax was 24 hours for bupivacaine, 36 hours for meloxicam, and 2 hours for DMSO. These systemic exposures were lower than observed with equivalent doses of HTX-011 in other surgical procedures, likely due to metabolic differences in postpartum women.
Conclusion: A single postpartum dose of HTX-011 (300 mg bupivacaine/9 mg meloxicam) in women undergoing Cesarean section resulted in very low (microgram) levels of bupivacaine, meloxicam, and DMSO in breast milk, as well as lower systemic exposure compared with previous HTX-011 studies. This suggests there may be a low risk for potential adverse effects on the breastfed child from maternal postpartum administration of HTX-011.