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1. 3-carboxamido-4-hydroxynaltrexone
1. 852626-89-2
2. Alks 33
3. Alks-33
4. Samidorphan [usan]
5. Rdc-0313-00
6. Chembl426084
7. Rdc-0313
8. Samidorphan (usan)
9. 7w2581z5l8
10. Alks-5461 Component Samidorphan
11. 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3-carboxamide
12. (1r,9r,10s)-17-(cyclopropylmethyl)-3,10-dihydroxy-13-oxo-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene-4-carboxamide
13. Morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxo-
14. Chembl471243
15. (4br,8as,9r)-11-(cyclopropylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5h-9,4b-(epiminoethano)phenanthrene-3-carboxamide
16. Samidorphan [usan:inn]
17. Alks33
18. Unii-7w2581z5l8
19. Rdc 0313
20. Samidorphan [inn]
21. Samidorphan [who-dd]
22. Schembl2786239
23. Ccdc 710249, Hcl Salt
24. Gtpl10651
25. Chebi:177605
26. Dtxsid401030402
27. Lybalvi (olanzapine + Samidorphan)
28. Bdbm50165049
29. Bdbm50278265
30. Compound 5 [pmid:15808478]
31. Db12543
32. D10162
33. Q7409428
34. 17-cyclopropylmethyl-3,10-dihydroxy-13-oxo-(1r,9r,10s)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene-4-carboxamide
| Molecular Weight | 370.4 g/mol |
|---|---|
| Molecular Formula | C21H26N2O4 |
| XLogP3 | 1.1 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 3 |
| Exact Mass | 370.18925731 g/mol |
| Monoisotopic Mass | 370.18925731 g/mol |
| Topological Polar Surface Area | 104 Ų |
| Heavy Atom Count | 27 |
| Formal Charge | 0 |
| Complexity | 665 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 3 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Covalently Bonded Unit Count | 1 |
Samidorphan is indicated in combination with [olanzapine] for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults.
Samidorphan, a novel opioid-system modulator, functions primarily as a -opioid receptor antagonist and as a /-opioid receptor partial agonist _in vitro_ with an overall profile consistent with a -opioid receptor antagonist _in vivo_ and is currently used to counteract [olanzapine]-induced adverse effects of weight gain and metabolic dysfunction. Samidorphin generally has a mild side effect profile. As an opioid antagonist, it can potentiate opioid withdrawal in dependent patients; it should not be administered within seven days from the last use of short-acting opioids and at least 14 days after cessation of long-acting opioids. Similarly, samidorphan use may lead to life-threatening opioid overdose, either in patients who attempt to overcome the samidorphan-induced opioid blockade or resume opioid use when therapy is interrupted or discontinued. Several other effects may be noted in combination with [olanzapine], including increased risk for potentially fatal cerebrovascular events in elderly patients with dementia-related psychosis, neuroleptic malignant syndrome, hyperprolactinemia, and tardive dyskinesia. [Olanzapine] is associated with an increased risk of metabolic dysfunction, including hyperglycemia, type II diabetes, dyslipidemia, and weight gain. Patients may be at increased risk for orthostatic hypotension and syncope, particularly in patients with known cardiovascular/cerebrovascular disease. Leukopenia, neutropenia, and agranulocytosis may occur and should be monitored for; patients with a history of seizure should also be monitored. This combination may exhibit anticholinergic (antimuscarinic) effects. It should be used with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, paralytic ileus, or related conditions. Serious allergic reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Patients may be at increased risk of cognitive and motor impairment; caution while operating machinery is recommended.
Absorption
Samidorphan pharmacokinetics are linear over the range of clinically relevant concentrations, and steady-state kinetics are reached by seven days with once-daily oral administration. Upon reaching steady-state, with a once-daily dose of 10 mg samidorphan combined with 20 mg [olanzapine], samidorphan has a mean Cmax of 45.1 11.4 ng/mL and an AUC24h of 364 112 ng\*h/mL. Samidorphan has an absolute oral bioavailability of 69% and a Tmax of 1-2 hours. Samidorphan pharmacokinetics are not significantly impacted by food; following a high-fat meal, the Cmax was 0.85 (90% CI 0.76, 0.94) and the AUC 1.03 (90% CI 1.0, 1.05) that for the fasted state.
Route of Elimination
Samidorphan is primarily renally excreted, with 67% of unchanged parent and metabolites eliminated in urine and another 16% in feces.
Volume of Distribution
Samidorphan following a single 10 mg oral dose had an apparent volume of distribution between 336.59 75.42 and 557.6 120.51 L, depending on age, gender, and concomitant food consumption.
Clearance
Samidorphan has a mean clearance of 35-45 L/h.
Samidorphan is primarily metabolized by CYP3A4, with minor contributions from CYP3A5, CYP2C19, and CYP2C8. The main metabolism products are RDC-9986 (an N-dealkylated metabolite) and RDC-1066 (an N-oxide metabolite); although both metabolites have a nanomolar affinity for the -, -, and -opioid receptors, neither is thought to contribute to the pharmacological effects of samidorphan.
Samidorphan has a mean half-life of 7-11 hours.
Samidorphan is a novel [naltrexone] analogue containing a 3-carboxamido group that functions as an opioid receptor modulator, both _in vitro_ and _in vivo_. Numerous _in vitro_ studies have demonstrated that samidorphan binds with high affinity to the -, -, and -opioid receptors with Ki values of 0.052 0.0044, 0.23 0.018, and 2.7 0.36 nM, respectively. Samidorphan acts as an antagonist at the -opioid receptor when it signals through Gi proteins, a partial agonist when the receptor signals through GoA, GoB, and Gz proteins, and essentially lacks -arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the - and -opioid receptors _in vitro_. In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the -, -, and -opioid receptors (Ki values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a -opioid receptor agonist and the latter as an antagonist. Overall, samidorphan functions primarily as a -opioid antagonist _in vivo_. [Olanzapine] is an efficacious antipsychotic whose use is limited, in part, by known adverse effects mediated through metabolic dysfunction: hyperglycemia/diabetes mellitus, hyperlipidemia, and weight gain. The exact mechanisms behind this metabolic dysfunction are incompletely understood, but it is known that opioid signalling is involved in feeding and metabolism. Clinical studies have demonstrated that the addition of samidorphan to [olanzapine] helps mitigate its metabolic-related adverse effects; presumably, this is due to opioid receptor signalling, though the exact mechanism remains to be determined. The appropriateness of samidorphan in combination therapy is due in part to its relatively mild side effect profile and low abuse potential.
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