Difelikefalin

Difelikefalin is a selective kappa opioid receptor agonist with low central nervous system penetration. The physicochemical properties of difelikefalin (hydrophilic, synthetic D-amino acid peptide with high polar surface area and charge at physiological pH) minimize its passive diffusion (permeability) and active transport across membranes, thus limiting penetration into the central nervous system.

The pathophysiology of chronic kidney disease-associated pruritus is thought to be multifactorial, including systemic inflammation and an imbalance in the endogenous opioid system (e.g., overexpression of mu opioid receptors and concomitant downregulation of kappa opioid receptors). Opioid receptors are known to modulate itch signals and inflammation, with kappa opioid receptor activation reducing itch and producing immunomodulatory effects.

The activation of kappa opioid receptors on peripheral sensory neurons and immune cells by difelikefalin are considered mechanistically responsible for the antipruritic and anti-inflammatory effects.

In patients with severe renal impairment undergoing haemodialysis, total body clearance of difelikefalin is reduced compared to healthy subjects and plasma concentrations decrease slowly until cleared during dialysis. Due to the 70-80% of difelikefalin removed during dialysis, difelikefalin is administered after each haemodialysis session in these patients. The available data on interindividual variability in haemodialysis subjects receiving 0.5 microgram/kg difelikefalin suggest that variability of AUC can exceed 30%.

Distribution

Plasma protein binding of difelikefalin is low to moderate, ranging from 24-32%, and remains unaffected by renal impairment. Mean volume of distribution at steady state ranged from 145 to 189 mL/kg in healthy subjects and from 214 to 301 mL/kg in haemodialysis patients with moderate-to-severe pruritus. Difelikefalin penetration into the central nervous system is limited (below limit of quantification) as shown by physico-chemical, in-vitro and animal data.

Elimination

In healthy subjects, the primary route of elimination for difelikefalin is renal, accounting for about 81% of the dose being excreted in urine as compared to 11% via faecal excretion. In both healthy volunteers and subjects on haemodialysis, most of the dose excreted into urine and faeces was unchanged difelikefalin with minor quantities of putative metabolites, none exceeding 2.5%. Mean total clearance ranged from 54 to 71 mL/h/kg and mean half-lives from 2 to 3 hours. By contrast, in renally impaired haemodialysis patients, elimination was predominantly via faeces, accounting on average for about 59% of the dose; about 19% were recovered in dialysate and about 11% were found in urine. As compared to subjects with normal renal function, mean total clearance decreased and half-lives increased about 10-fold with ranges of 5.3 to 7.5 mL/h/kg and 23 to 31 hours, respectively.

Interaction with other medicinal products

Difelikefalin is neither a substrate for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, nor an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 and has minimal to no potential for induction of human CYP1A2, CYP2B6, or CYP3A. It is not an inhibitor of glucuronidation enzymes either (UGT1A3, UGT1A9, or UGT2B7).

In addition, difelikefalin is not an inhibitor of BCRP, BSEP, LAT1, MATE1, MATE2-K, MRP2, OAT1, OAT3, OATP1A2, OATP1B1, OATP1B3, OCT1, OCT2, OCT3, P-glycoprotein, PEPT1 or PEPT2, and is not a substrate for ASBT, BCRP, BSEP, LAT1, MATE1, MATE2-K, MRP2, OAT1, OAT2, OAT3, OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT2, OCT3, OCTN1, OCTN2, OSTαβ, P-glycoprotein, PEPT1 or PEPT2.

Linearity/non-linearity

Pharmacokinetics of difelikefalin were demonstrated to be linear and dose-proportional in healthy subjects (tested over dose ranges of 1 to 40 and 1 to 20 micrograms/kg in single and repeated dose studies, respectively). Steady state dose proportionality was also established in chronic kidney disease patients on haemodialysis receiving repeated doses from 0.5 to 2.5 micrograms/kg, 3 times per week for 1 week. However, in another study dose proportionality was observed at doses of 0.5 and 1 micrograms/kg, but not at the dose of 1.5 micrograms/kg. Trough plasma concentration values reached steady state by the second dose and for the dose of 0.5 micrograms/kg, mean accumulation ratio was 1.144 in one study based on AUC_0-48h and 1.33 in another study, based on AUC_0-44h; showing that variability for accumulation parameters can exceed 30%.

Characteristics in specific groups of subjects or patients

Based on available evidence, there is no indication that factors such as age, sex, ethnicity, or mild to moderate hepatic impairment have any impact on the pharmacokinetics of difelikefalin.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity and carcinogenic potential.

Reproductive toxicity

In rats, male and female fertility, early embryonic, and prenatal and postnatal development were not affected up to 2000-fold the human AUC. In the rabbit, prenatal development was neither impaired despite marked maternal toxicity at 30-fold the human AUC.

Difelikefalin crosses the placenta in rats.

Abuse and dependence potential

The abuse and dependence potential studies in the rat suggest that difelikefalin is not likely to present a risk of physical dependence or abuse potential.