The introduction of peripherally acting μ-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation brought opportunity for improved health and quality of life for patients on long-term opioid therapy.

Constipation is a bothersome, common, and underrecognized adverse effect (AE) of long-term opioid therapy. PAMORAs offer treatment for this condition and can improve patient adherence to the prescribed opioid therapy. However, it is crucial to understand the pharmacokinetic differences between the PAMORAs to aid in AE monitoring and minimize potentially strong drug-drug interactions (DDIs).1

The 3 PAMORAs on the US market indicated for treating opioid-induced constipation from long-term opioid use are methylnaltrexone, naldemedine, and naloxegol. Each agent is available as oral tablets, and methylnaltrexone is also available as a subcutaneous injection. PAMORAs work by inhibiting the action of opioids in the gastrointestinal tract by combining with μ-receptors, thereby decreasing the constipating effects of opioids without compromising the analgesic effects in the central nervous system. These medications do not interfere with analgesia or cause opioid withdrawal, as they cannot cross the blood-brain barrier (BBB), because of their increased efflux across the BBB, large chemical structure, lipid solubility, and/or reduced permeability.1 Despite their overlapping mechanisms of action, the 3 PAMORAs differ in their pharmacokinetic properties. These properties can be harnessed based on a patient’s concomitant medications to help mitigate the risk of clinically relevant DDIs. The article “Peripheral Opioid Receptor Antagonists for Opioid-Induced Constipation: A Primer on Pharmacokinetic Variabilities with a Focus on Drug Interactions,” evaluates the subtle pharmacokinetic differences among these PAMORAs.1

PAMORA DDIs may occur when a drug alters the absorption, distribution, metabolism, or elimination of another drug,2 such as with cytochrome P450 enzymes and P-glycoprotein (P-gp), the latter of which has significance within the gut and passage through the BBB. Evaluating each PAMORA’s unique profile can assist clinicians in selecting the optimal therapy for their patients, especially those with polypharmacy.

METHYLNALTREXONE
Study results have shown that methylnaltrexone does not significantly inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4 enzymes. Methylnaltrexone is metabolized by CYP2D6 to a small extent. However, this has no relevance nor is it affected by drug interactions. In healthy volunteers, methylnaltrexone did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. Cimetidine is a moderate CYP3A4 inhibitor, and in healthy adults, cimetidine did not cause a clinically significant increase in the systemic exposure of methylnaltrexone.3 Therefore, methylnaltrexone’s pharmacokinetic profile is not affected by DDIs in a clinically significant manner (Table).



NALOXEGOL
Naloxegol is a substrate of P-gp and is mainly metabolized by CYP3A4 enzymes. Moderate and strong CYP3A4 inhibitors significantly increase the plasma concentration of naloxegol, therefore potentiating the risk of AEs. In fact, concomitant use of naloxegol and strong CYP3A4 inhibitors, such as clarithromycin, itraconazole, and ketoconazole is contraindicated.4 Increasing the plasma concentration of naloxegol may precipitate opioid withdrawal symptoms. Similarly, moderate CYP3A4 inhibitors, such as diltiazem, erythromycin, and verapamil, should be avoided when using naloxegol. If coadministration of moderate CYP3A4 inhibitors cannot be avoided, naloxegol dose reduction is recommended, along with monitoring for toxicity, including opioid withdrawal symptoms, such as chills, diarrhea, hyperhidrosis, and irritability.

On the other hand, CYP3A4 inducers and P-gp inducers have not been shown to significantly decrease the plasma concentration of naloxegol. For example, efavirenz, a moderate CYP3A4 inducer, does not affect the concentration of naloxegol, whereas rifampin, a strong CYP3A4 inducer, may slightly decrease the exposure of naloxegol (but clinical significance has not been established) (Table). In healthy subjects, morphine and its major metabolites were not affected by naloxegol.1,4,5

NALDEMEDINE
Although naldemedine is a substrate of CYP 3A4, it does not inhibit or induce CYP450 enzymes and does not inhibit P-gp. To prevent decreased efficacy, coadministration of naldemedine and strong CYP3A4 inducers, such as rifampin, should be avoided. Decreasing naldemedine’s dose to counteract the effects of rifampin is not recommended, as it puts the patient at risk of gastrointestinal-related AEs. CYP3A4 inhibitors and P-gp inhibitors moderately increase the plasma concentration of naldemedine but dose adjustments are not recommended (Table). In this case, clinicians should monitor for AEs, such as abdominal pain, diarrhea, and nausea.1,6,7

PAMORAs can interact with other medications, resulting in decreased efficacy or toxicity. Understanding the pharmacokinetic relationship between each PAMORA and other medications could affect drug selection. Pharmacists play a pivotal role in identifying and preventing DDIs. Their detailed knowledge about drugs allows them to educate caregivers, health care professionals, and patients regarding clinically significant drug interactions. They can assist clinicians with therapy selection, as well as recommend appropriate course of action when DDIs occur. As a key part of the health care team, pharmacists can equip patients with knowledge about potential AEs, expectations, goals of therapy, and interactions to ensure safe medication administration.
 
Himayapsill Batista Quevedo, PharmD, is a PGY-1 pharmacy resident at Corporal Michael J. Crescenz VA Medical Center in Philadelphia, Pennsylvania.

Amelia L. Persico, Pharm D, MBA, is a PGY-2 pain and palliative care pharmacy resident at Stratton VA Medical Center in Albany, New York.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is president of Remitigate Therapeutics, LLC and the managing editor and owner of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences in Albany, New York, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.



REFERENCES
  1. Gudin J, Fudin J. Peripheral opioid receptor antagonists for opioid-induced constipation: a primer on pharmacokinetic variabilities with a focus on drug interactions. J Pain Res. 2020;13:447-456 doi:10.2147/JPR.S220859
  2. Gunaratna C. Drug metabolism & pharmacokinetics in drugdiscovery: a primer for bioanalytical chemists, part I. Curr Sep.2000;19(1):17-23.
  3. Relistor. Prescribing information. Salix Pharmaceuticals, Inc; 2014. Accessed May 26, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2014/021964s010lbl.pdf
  4. Movantik. Prescribing information. AstraZeneca Pharmaceuticals; 2020. Accessed May 26, 2020. azpicentral.com/movantik/movantik.pdf
  5. Zhou D, Bui K, Sostek M, Al-Huniti N. Simulation and prediction of the drug–drug interaction potential of naloxegol by physiologically based pharmacokinetic modeling. CPT Pharmacometrics Syst Pharmacol. 2016;5(5):250-257. doi:10.1002/psp4.12070
  6. Symproic. Prescribing information. Shionogi, Inc; 2017. Accessed May 26, 2020. symproic.com/docs/symproic-PI.pdf
  7. Naldemedine clinical pharmacology and biopharmaceutics review. Center for Drug Evaluation and Research. Published 2008. Accessed March 30, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021964s000_PharmR_P1.pdf