Pharmacokinetics of difelikefalin is proportional to the dose and the range over a single dose between 1 and 3 mcg/kg which is 2 to 6 times the required dose. 0.5 to 2.5 mcg/kg multiple intravenous dosage range and these 1 to 5 times the required dosage in CKD patients with ongoing hemodialysis treatment. Upon second dosage administration, the mean accumulation ratio increased to 1.6 hence reaching a steady state. According toCowan et al., (2015), difelikefalin distribution mean volume is about 238 mL per kg and the binding to plasma proteins among the patients with ongoing dialysis is 23% to 28%. Its half-life ranges between 23 and 31 hours. A radiolabeled difelikefalin had a circulation of >99% of plasma. The plasma concentrations of difelikefalin are reduced by 70% to 80% by hemodialysis and it cannot be detected in plasma after 2 circles of dialysis. In vitro studies demonstrated that it is not metabolized by cytochrome P450 (C.Y.P.) enzymes CYP3A, CYP2D6, CYP2C9, CYP2C8, CYP2C19 or CYP1A2. Following administration of difelikefalin to H.D. patients, excretion on urine is 11% of the administered difelikefalin dose, in feces it is 59%, and in dialysate fluid it is at 20% in patients undergoing hemodialysis.
The most common adverse reactions noted by Kremer et al., 2020 were changes in the mental status, somnolence, headache, gait disturbances, dizziness, nausea, diarrhea, and hyperkalemia.
Aldrich, J. V., & McLaughlin, J. P. (2021). Peptide Kappa Opioid Receptor Ligands and Their Potential for Drug Development.
Che, T., & Roth, B. L. (2021). Structural insights accelerate the discovery of opioid alternatives. Annual Review of Biochemistry, 90.
Cowan, A., Kehner, G. B., & Inan, S. (2015). Targeting itch with ligands selective for κ opioid receptors. Pharmacology of itch, 291-314.
Deeks, E. D. (2021). Difelikefalin: First Approval. Drugs, 1-8.
Fishbane, S., Jamal, A., Munera, C., Wen, W., & Menzaghi, F. (2020). A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. New England Journal of Medicine, 382(3), 222-232.
Floettmann, E., Bui, K., Sostek, M., Payza, K., & Eldon, M. (2017). Pharmacologic profile of naloxegol, a peripherally acting µ-opioid receptor antagonist, for the treatment of opioid-induced constipation. Journal of Pharmacology and Experimental Therapeutics, 361(2), 280-291.
Gardell, L. R., Spencer, R. H., Chalmers, D. T., & Menzaghi, F. (2008). Preclinical profile of CR845: A novel, long-acting peripheral kappa-opioid receptor agonist. Poster Presentation at the International Association for the Study of Pain.
Hesselink, J. M. K. (2017). CR845 (Difelikefalin), A Kappa Receptors Agonist In Phase III By CARA Therapeutics: A Case Of ‘Spin’In Scientific Writing?. J Pharmacol Clin Res, 2, 555588.