Naloxegol is metabolized primarily by the CYP P450 3A4 enzyme system and undergoes enterohepatic recycling. In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and feces. These metabolites were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. Human metabolism data suggests absence of major metabolites. The activity of the metabolites at the opioid receptor has not been determined.
Naloxegol is metabolized primarily by the CYP3A enzyme system. In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and feces. These metabolites were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. Human metabolism data suggests absence of major metabolites. The activity of the metabolites at the opioid receptor has not been determined.
Therapy with naloxegol has not been linked to serum enzyme elevations or to clinically apparent liver injury. In preregistration studies, liver test abnormalities arose in less than 1% of treated patients but were transient, mild and not associated with symptoms. There were no reported cases of liver injury with jaundice or symptoms. Since its approval and more widescale use, there have been no published reports of hepatotoxicity attributed to naloxegol.
Naloxegol is a PEGylated, oral, peripherally acting mu-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.
... This study evaluated the effects of CYP3A inhibition and induction on the PK, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers. Area under the curve (AUCinf ) for naloxegol was increased with coadministration of either ketoconazole (12.9-fold) or diltiazem (3.4-fold) and decreased by 89% with coadministration of rifampin compared with AUCinf for naloxegol alone. Naloxegol was generally safe and well tolerated when given alone or coadministered with the respective CYP3A modulators; one subject discontinued because of elevations in liver enzymes attributed to rifampin. The exposure of naloxegol was affected substantially by ketoconazole, diltiazem, and rifampin, suggesting that it is a sensitive in vivo substrate of CYP3A4.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
圣约翰草的同时使用可能导致纳洛昔戈尔暴露量显著降低，因此应避免使用。
Concomitant use of St. John's wort may lead to significant decrease in naloxegol exposure and, therefore, should be avoided.
Grapefruit juice has been classified as a CYP3A4 inhibitor. Concomitant consumption of grapefruit or grapefruit juice while taking Movantik should be avoided.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
吸收
口服给药后，纳洛昔戈尔在不到2小时内达到峰值浓度（Cmax）。
Following oral administration, naloxegol is absorbed with peak concentrations (Cmax) achieved in less than 2 hours.
来源:DrugBank
吸收、分配和排泄
消除途径
粪便：口服给药后68%。尿液：口服给药后16%。
Feces: 68% after oral administration. Urine: 16% after oral administration.
The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 L to 2140 L across dosing groups and studies. Plasma protein binding of naloxegol in humans was low (approximately 4.2%).
The present invention relates to solid dispersion of Naloxegol oxalate. Further, the present invention relates to an improved process for Naloxegol oxalate and intermediates thereof.
[EN] AN IMPROVED PROCESS FOR THE PREPARATION OF (5Α,6Α)-17-ALLYL-6-(2,5,8,11,14,17,20- HEPTAOXADOCOSAN-22-YLOXY)-4,5-EPOXYMORPHINAN-3,14-DIOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION DE (5Α,6Α)-17-ALLYL-6-(2,5,8,11,14,17,20-HEPTAOXADOCOSAN-22-YLOXY) -4,5-ÉPOXYMORPHINANE-3,14-DIOL ET DE SES SELS PHARMACEUTIQUEMENT ACCEPTABLES
申请人：MSN LABORATORIES PRIVATE LTD R&D CENTER
公开号：WO2019058387A1
公开（公告）日：2019-03-28
The present invention relates to an improved process for the preparation of (5α, 6α)-17-allyl-6-(2, 5, 8, 11, 14, 17, 20- heptaoxadocosan-22-yloxy)-4, 5-epoxymorphinan-3, 14-diol which is represented by the following structural formula-1 or its pharmaceutically acceptable salts and also provides an improved process for the purification of the compound of formula-1 and its oxalate salt.
The present invention relates to a solid dispersion comprising, preferably consisting of, naloxegol salts in amorphous form and at least one pharmaceutically acceptable matrix compound and wherein the matrix compound is
(i) an organic polymer, or
(ii) a silicon-based inorganic adsorbent.
Further, the present invention also relates to a process for preparing a solid dispersion comprising naloxegol in amorphous form and at least one pharmaceutically acceptable matrix compound, as well as to a solid dispersion obtained or obtainable by said process. Further, the present invention relates to a pharmaceutical composition comprising such solid dispersion as well as a pharmaceutical composition for use as µ-opioid antagonists.
本发明涉及一种固体分散体，该分散体最好由无定形形式的纳洛酮盐和至少一种药学上可接受的基质化合物组成，其中基质化合物是
(i) 有机聚合物，或
(ii) 硅基无机吸附剂。
此外，本发明还涉及一种制备包含无定形形式的纳洛酯和至少一种药学上可接受的基质化合物的固体分散体的工艺，以及通过所述工艺获得或可获得的固体分散体。此外，本发明还涉及一种包含这种固体分散体的药物组合物以及一种用作μ-阿片类拮抗剂的药物组合物。
Naloxegol oxalate and solid dispersion thereof
申请人：AUROBINDO PHARMA LIMITED
公开号：US11077103B2
公开（公告）日：2021-08-03
The present invention relates to solid dispersion of Naloxegol oxalate. Further, the present invention relates to an improved process for Naloxegol oxalate and intermediates thereof.
