Pharmacokinetics and tolerability of intranasal or intravenous administration of nalbuphine in infants.

OBJECTIVES: Intranasal nalbuphine could be a safe, efficacious and non-invasive alternative to parenteral pain medication in infants. We aimed to assess pharmacokinetics (PK) and tolerability of intranasal and intravenous nalbuphine administration in infants. METHODS: Prospective open-label study including infants 1-3 months of age admitted to the emergency department, receiving nalbuphine for procedural pain management. Patients were alternately allocated to a single nalbuphine dose of 0.05 mg/kg intravenously or 0.1 mg/kg intranasally. Nalbuphine PK samples were collected 15, 30 and 120-180 min after dosing. Area under the concentration time curve (AUC0-Tlast) was calculated by non-compartmental analysis (NCA) and compared by Wilcoxon test. Neonatal Infant Pain Score was assessed during nalbuphine administration and the following interventions: venous access, urinary catheterisation, lumbar puncture. RESULTS: Out of 52 study subjects receiving nalbuphine, 31 were eligible for NCA (11 intravenous, 20 intranasal). Median AUC0-Tlast after 0.05 mg/kg intravenously was 8.7 (IQR: 8.0-18.6) µg×L/hour vs 7.6 (5.4-10.4) µg×L/hour after intranasal administration of 0.1 mg/kg (p=0.091). Maximum serum concentration (Cmax) was observed 30 min after intranasal administration (3.5-5.6 µg/L). During intravenous and intranasal nalbuphine administration, mild to no pain was recorded in 71% and 67% of study subjects, respectively. CONCLUSION: This is the first study investigating intranasal administration of nalbuphine in infants suggesting an intranasal bioavailability close to 50%. Non-invasive intranasal application was well tolerated. Additional studies are warranted to optimise dosing and timing of interventions as Cmax is delayed by half an hour after intranasal administration. TRIAL REGISTRATION NUMBER: NCT03059511.

Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants.

Objectives: The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1-3 months old. Methods: PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold). Results: Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26-56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min. Conclusion: This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1-0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.