Oliceridine

Oliceridine, marketed under the brand name Olinvyk, is an intravenous opioid analgesic approved by the FDA for use in adult patients. It is designed to provide rapid pain relief in controlled clinical settings.

Olinvyk is indicated for the management of moderate to severe acute pain severe enough to require an opioid and for which alternative treatments are inadequate. It offers an option when standard pain therapies, such as nonsteroidal anti-inflammatory drugs or less potent opioids, do not provide sufficient relief.

Mechanistically, oliceridine is a G protein–biased μ-opioid receptor agonist. By preferentially activating G protein signaling over β-arrestin pathways, oliceridine aims to deliver effective analgesia with a potentially reduced risk of certain opioid-related adverse effects.

The CYP2D6 gene encodes the cytochrome P450 2D6 enzyme, which plays a key role in the metabolism of many medications, including opioids like oliceridine. Variants in CYP2D6 can range from no function to increased function, categorizing individuals into different metabolizer phenotypes.

Changes in CYP2D6 activity affect how quickly oliceridine is processed by the liver. Increased activity can lead to faster clearance and potentially lower drug levels, while decreased activity may slow metabolism and raise systemic exposure, impacting both efficacy and safety.

Genetic variations in CYP2D6 result in distinct metabolizer phenotypes that influence systemic exposure, efficacy, and risk of adverse effects when taking oliceridine. Individuals classified as ultrarapid metabolizers clear the drug more quickly, potentially reducing analgesic effectiveness, while poor metabolizers may have higher drug levels, increasing the risk of sedation and respiratory depression. Intermediate and normal metabolizer groups generally exhibit expected responses with standard dosing. For genotypes that cannot be determined or lack available information, the impact remains unknown, and standard dosing with clinical monitoring is advised.

Depending on CYP2D6 metabolizer status, patients may experience differences in oliceridine’s effectiveness and safety profile. Below are the clinical effects associated with each phenotype group:

Ultrarapid Metabolizer

• Effect on drug levels: Decreased systemic exposure due to rapid metabolism.
• Clinical consequence: Potentially reduced analgesic efficacy.
• Side effects: Typical opioid side effects; no increased risk identified (severity is standard; frequency unknown).

Normal Metabolizer

• Effect on drug levels: Expected systemic exposure with standard metabolism.
• Clinical consequence: Anticipated efficacy and safety with standard dosing.
• Side effects: Common opioid side effects (e.g., nausea, constipation); severity and frequency as in general population.

Intermediate Metabolizer

• Effect on drug levels: Slightly increased exposure due to reduced metabolism.
• Clinical consequence: Possible mild increase in opioid effects.
• Side effects: Mild sedation or respiratory effects; severity typically mild; frequency unknown.

Poor Metabolizer

• Effect on drug levels: Increased systemic exposure due to slow metabolism.
• Clinical consequence: Higher risk of respiratory depression and sedation.
• Side effects: Increased frequency and severity of sedation and respiratory depression.

Indeterminate/Not Available

• Effect on drug levels: Unknown due to insufficient genotype information.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
• Side effects: Unknown; monitor for typical opioid-related adverse effects.

The following dosing guidelines are based on FDA recommendations for oliceridine and CYP2D6 metabolizer phenotypes.

CYP2D6 Dosing Guideline

The FDA guidance for oliceridine does not specify alternative medications or dosing strategies based on CYP2D6 phenotype. Clinicians may consider opioids that are less dependent on CYP2D6 metabolism, such as morphine or hydromorphone, though individual clinical judgment and patient-specific factors should guide any alternative selection.

• FDA – Table of Pharmacogenetic Associations