Naldebain Mechanism of Action

Pharmacology: Mechanism of Action: Dinalbuphine sebacate is a synthetic nalbuphine prodrug. The dosage form is a sterile oil solution, which is suitable for intramuscular injection. Dinalbuphine sebacate contains two nalbuphine molecules joined by sebacoyl ester which is rapidly hydrolyzed to nalbuphine by esterase. Nalbuphine is the active moiety.
Nalbuphine is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on milligram basis. Receptor studies show that nalbuphine binds to mu, kappa, and delta receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/partial mu antagonist analgesic.
Pharmacodynamics: The pharmacodynamics of dinalbuphine sebacate is from nalbuphine.
Nalbuphine may produce the same degree of respiratory depression as equianalgesic doses of morphine. However, nalbuphine exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression in the absence of other CNS active medications affecting respiration.
Nalbuphine by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reverse or block opioid-induced respiratory depression from the mu agonist analgesic. Nalbuphine may precipitate withdrawal in patients dependent on opioid drugs. NALDEBAIN should be used with caution in patients who have been receiving mu opioid analgesics on a regular basis.
Clinical Studies: A multicenter, randomized, double-blind, placebo-controlled phase III study evaluated the safety and efficacy of 150 mg NALDEBAIN in patients undergoing hemorrhoidectomy. There are 78 subjects in NALDEBAIN group while 78 subjects in placebo group. 24±12 hrs prior to hemorrhoidectomies, the subjects were treated with single IM injection of NALDEBAIN 150 mg. The post-operative analgesics were PCA dosing with ketorolac as needed for the fast two days (Day 1 and 2) and oral dosing with ketorolac as needed for the following 5-8 days (Day 3 to 10). The primary objective of this study is pain assessment (time-specific pain intensity) calculated as the area under the curve (AUC) of VAS pain intensity scores through 48 hours after surgery (AUC_0-48). There was a significant treatment effect for NALDEBAIN compared to placebo (p=0.0016) (see Figure 1).
In this clinical study, NALDEBAIN demonstrated a significant reduction in pain intensity compared to placebo for up to 48 hours after surgery, equals to 72 hours after administration. The difference in mean pain intensity between treatment groups occurred during the 24 and 48 hours after surgery, which means following 48 and 72 hours study drug administration. Subjects treated with NALDEBAIN took significantly longer periods of time for the first use of Ketorolac via PCA than those in placebo group, 10.90 hours in NALDEBAIN group, 5.90 hours in placebo group. Figure 2 shows the probability of subjects who does not use the PCA within 48 hours after surgery. The total amount of Ketorolac administered by PCA through 48 hours after surgery in NALDEBAIN group is 43.04 mg while in placebo group is 77.81 mg. From Day 3 to Day 7 after surgery, there was a significant decrease in oral analgesics consumption, 47.95 mg in NALDEBAIN group, 67.05 mg in placebo group. The results for assessments of pain intensity measured with VAS scores during Day 3-7 listed in Table 1. Besides, in post-hoc analysis, pain assessment during Day 3-7 was calibrated for the use of rescue medication as that was done for the primary end point. After calibration, the pain intensity (VAS scores) in NALDEBAIN group is less than placebo group. In post-hoc analysis, there was difference between NALDEBAIN and placebo treatments on VAS AUC_0-final (see Figure 3). (See Figures 1 and 2, Tables 1 and 2 and Figure 3.)

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Pharmacokinetics: Absorption: Following intramuscular administration 150 mg of dinalbuphine sebacate, the drug is absorbed and rapidly hydrolyzed as nalbuphine with peak concentrations (C_max) achieved at 64.0±9.3 hours. The mean C_max is estimated to be 15.4±6.4 ng/mL.
Metabolism: Dinalbuphine sebacate is metabolized primarily by esterase. Biotransformation studies showed that over 90% of the prodrug was converted to nalbuphine in about 30 min in fresh human whole blood.
Nalbuphine is metabolized by Cytochrome P450s and phase II enzyme UGTs (uridinyl diphosphate glucuronosyltransferases) and produce glucuronide metabolites.
Distribution: The mean apparent volume of distribution in healthy volunteers after administration 150 mg NALDEBAIN is estimated to be 10628 ± 4403 L.
In vitro plasma protein binding study suggest that dinalbuphine sebacate protein binding is about 90% in human plasma.
Dinalbuphine sebacate and nalbuphine did partition into red blood cells but not to a greater extent than to plasma. The RBC partition coefficients, K_RBC/PL, for dinalbuphine sebacate determined to be 1.20; nalbuphine determined to be 1.24.
Excretion: Nalbuphine is mainly excreted by the kidneys. Following intramuscular administration 150 mg of dinalbuphine sebacate, the drug is absorbed and rapidly hydrolyzed as nalbuphine. The elimination half-life of nalbuphine was 83.2±46.4 hr. Mean clearance of nalbuphine is 100±11 L/h. Less than 4% nalbuphine of each dose was recovered in urine.
Drug Interaction: No drug interaction studies have been conducted [see Interactions].
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: No carcinogenesis study was conducted with dinalbuphine sebacate. According to reference, long term carcinogenicity studies were performed in rats (24 months) and mice (19 months) by oral administration at doses up to 200 mg/kg (1180 mg/m²) and 200 mg/kg (600 mg/m²) per day, respectively. There was no evidence of an increase in tumors in either species related to nalbuphine administration.
Mutagenesis: Dinalbuphine sebacate did not show genotoxic activity in the in vivo mouse peripheral blood micronucleus assay.
According to reference, nalbuphine did not have mutagenic activity in the AMES test with four bacterial strains, in the Chinese Hamster Ovary HGPRT assays or in the Sister Chromatids Exchange Assay. However, nalbuphine induced an increased frequency of mutation in the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test of the cytogenicity bone marrow assay in rats.
Impairment of Fertility: No reproduction toxicity study was conducted with dinalbuphine sebacate. In reproductive and developmental toxicity studies in rats, nalbuphine did not affect fertility at subcutaneous doses up to 56 mg/kg/day or 330 mg/m²/day.