Samidorphan

Samidorphan Uses, Dosage, Side Effects, Food Interaction and all others data.

Olanzapine is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes. Samidorphan is a novel opioid antagonist structurally related to naltrexone, with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing. Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate olanzapine-induced weight gain and metabolic dysfunction.

Samidorphan was first approved as a variety of fixed-dose combination tablets with olanzapine by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.

Samidorphan, a novel opioid-system modulator, functions primarily as a μ-opioid receptor antagonist and as a κ/δ-opioid receptor partial agonist in vitro with an overall profile consistent with a μ-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.

Samidorphan
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Samidorphan
Generic	Samidorphan
Samidorphan Other Names	Samidorphan
Type
Formula	C₂₁H₂₆N₂O₄
Weight	Average: 370.449 Monoisotopic: 370.189257325
Protein binding	Samidorphan is between 23 and 33 percent bound to plasma proteins.
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

Uses

Samidorphan is a novel opioid-system modulator, similar to naltrexone, that functions primarily as a μ-opioid receptor antagonist in vivo and is used primarily in combination with antipsychotics to reduce their metabolic dysfunction-associated adverse effects.

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 is also used to associated treatment for these conditions: Bipolar 1 Disorder, Bipolar Disorder With Manic or Mixed Episodes, Schizophrenia

How Samidorphan works

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 μ-, κ-, and δ-opioid receptors with K_i values of 0.052 ± 0.0044, 0.23 ± 0.018, and 2.7 ± 0.36 nM, respectively. Samidorphan acts as an antagonist at the μ-opioid receptor when it signals through G_αi proteins, a partial agonist when the receptor signals through G_αoA, G_αoB, and G_αz proteins, and essentially lacks β-arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the κ- and δ-opioid receptors in vitro. In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the μ-, κ-, and δ-opioid receptors (K_i values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a μ-opioid receptor agonist and the latter as an antagonist. Overall, samidorphan functions primarily as a μ-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.

Toxicity

There is limited information regarding samidorphan overdose. During clinical trials for the combination of olanzapine and samidorphan, overdose was recognized in 7/861 patients, none of which were fatal. One patient who ingested 5.5- and 11-times the maximum daily dosage of olanzapine and samidorphan, respectively, was unresponsive and admitted to the hospital but stabilized within two days. As there are no known antidotes for overdose with this combination, symptomatic and supportive measures are recommended.

Food Interaction

Take with or without food. Food has only a minor effect on samidorphan pharmacokinetics.

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.

Elimination Route

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 C_max of 45.1 ± 11.4 ng/mL and an AUC_24h of 364 ± 112 ng*h/mL. Samidorphan has an absolute oral bioavailability of 69% and a T_max of 1-2 hours.

Samidorphan pharmacokinetics are not significantly impacted by food; following a high-fat meal, the C_max 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.