A dual system platform for drug metabolism: Nalbuphine as a model compound

Liang, Ren-Jong; Shih, Yin-Ning; Chen, Yen-Lun; Liu, Weiyang; Yang, Wanling; Lee, Shih‐Yu; Wang, Hong-Jaan

doi:10.1016/j.ejps.2019.105093

Cited by 12 publications

(14 citation statements)

References 35 publications

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“…This suggests that maturation of nalbuphine metabolic pathways is almost complete at the age of 1–3 months. Human in vivo experiments had shown that the ratio of metabolite production in nalbuphine via CYPs and UGTs is ~23:77 ( 11 ). However, no general developmental pattern for the individual UGT isoforms is currently available.…”

Section: Discussionmentioning

confidence: 99%

“…As the drug undergoes extensive and variable first-pass metabolism, nalbuphine is usually given parenterally ( 1 , 4 , 8 ). The metabolism of nalbuphine involves phase I oxidation–reduction via Cytochrome P450 to 25% ( via CYP2C9 and CYP2C19) and phase II glucuronidation via UDP-glucuronosyltransferases to 75% (UGT2B7, UGT1A3, and UGT1A9) ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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ObjectivesThe 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.MethodsPPK 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).ResultsThirty-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.ConclusionThis 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…7 Therefore, it is usually administered intravenously in clinical practice, which takes effect quickly and maintains activity for approximately 3-6 h with a half-life of 2-5 h. 8 Nalbuphine is extensively metabolized by Uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B7, UGT1A3, cytochrome P450 (CYP) 2C9 and CYP2C19 in the liver, yielding two hydroxylated derivatives and two conjugated metabolites. 9,10 The metabolites are mainly excreted into the feces, and approximately 7% of the unbound nalbuphine is excreted in the urine. 1 Liver impairment is a major global problem affecting human health.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction

Gao¹,

Nie²,

Gao³

et al. 2022

DDDT

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This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction. Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software. Results: Compared with the normal liver function group, the plasma elimination half-life (T 1/2 ) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P<0.05), and the volume of distribution (V d ) increased by approximately 85% (100.08 L vs 184.95 L, P<0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T 1/2 , and weight associated with area under the curve (AUC (0→∞) ) independently. Conclusion:The T 1/2 , mean residence time, and V d of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.

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“…Although nalbuphine has been approved more than 20 years ago, pharmacokinetic (PK) data on the drug remain limited, especially in children 2–4 12 14–16. The drug is mainly hepatically metabolised involving several phase I and phase II pathways 17. As a drug with high hepatic extraction, substantial and variable first-pass metabolism limits its oral use 1 3 15.…”

Section: Introductionmentioning

confidence: 99%

“… 2–4 12 14–16 The drug is mainly hepatically metabolised involving several phase I and phase II pathways. 17 As a drug with high hepatic extraction, substantial and variable first-pass metabolism limits its oral use. 1 3 15 Half-life in adults is 2.5–3 hours 1 and similar in children.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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ObjectivesIntranasal 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.MethodsProspective 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.ResultsOut 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.ConclusionThis 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 numberNCT03059511.

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A dual system platform for drug metabolism: Nalbuphine as a model compound

Cited by 12 publications

References 35 publications

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

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

Pharmacokinetic Study of Nalbuphine in Surgical Patients Undergoing General Anesthesia with Varying Degrees of Liver Dysfunction

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

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