Naldemedine

Naldemedine is an antagonist of opioid binding at the mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without reversing the central nervous system (CNS)-mediated opioid effects.

Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB); the CNS penetration of naldemedine is expected to be negligible at the recommended dose. Additionally, naldemedine is a substrate of the P-glycoprotein (P-gp) efflux transporter, which may also be involved in reducing naldemedine penetration into the CNS. Based on this, naldemedine is expected to exert its anti-constipating effects on opioids without reversing their CNS-mediated analgesic effects.

Absorption

Naldemedine is absorbed with a time to achieve peak plasma concentration of approximately 0.75 hours in the fasted state. The absolute bioavailability of naldemedine has not been established. The absolute bioavailability of naldemedine is estimated to be in the range of 20% to 56%.

There is no clinically significant food effect. The peak plasma concentration was reduced by 35% and time to achieve peak plasma concentration was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas no significant difference was observed in the area under the plasma concentration-time curve by food intake. Based on these data, naldemedine can be taken with or without food.

Distribution

Naldemedine is highly bound to serum proteins, predominantly to human serum albumin and to a lesser extent to α1-acid-glycoprotein and γ-globulin, with a mean protein binding ratio in humans of 93.2%. The apparent volume of distribution is approximately 155 litres.

Biotransformation

Naldemedine is primarily metabolized by CYP3A to nor-naldemedine, with a minor contribution from UGT1A3 to form naldemedine 3-G.

Following oral administration of [¹⁴C]-labelled naldemedine, the primary metabolite in plasma was nor-naldemedine, with a relative exposure compared to naldemedine of approximately 9 to 13%. Naldemedine 3-G was a minor metabolite in plasma, with a relative exposure to naldemedine of less than 3%.

Naldemedine also undergoes cleavage in the gastrointestinal tract to form benzamidine and naldemedine carboxylic acid.

In in vitro studies at clinically relevant concentrations, naldemedine did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or CYP4A11 isozymes) and is not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, BCRP, P-gp, MATE1, MATE2-K or BSEP transporters. Naldemedine did not cause significant induction of CYP1A2, CYP2B6 or CYP3A4 isozymes. Therefore, treatment with naldemedine is not expected to alter the pharmacokinetics of co-administered medicines that are substrates of these enzymes and transporters.

Elimination

The apparent terminal elimination half-life of naldemedine is approximately 11 hours, and the apparent total clearance (CL/F) of naldemedine is 8.4 L/h. Following oral administration of radio- labelled naldemedine, 57.3% and 34.8% of the dose was excreted in urine and faeces for the [oxadiazole-¹⁴C] - naldemedine and 20.4% and 64.3% of the dose was excreted as the [carbonyl-¹⁴C] - naldemedine in urine and faeces, respectively. Approximately 20% of the naldemedine dose is excreted unchanged in urine.

Linearity/non-linearity

The peak plasma concentration and area under the plasma concentration-time curve increased in an almost dose-proportional manner within the dose range of 0.1 to 100 mg. A slight accumulation (1 to 1.3-fold) for peak plasma concentration and area under the plasma concentration–time curve was observed after once daily multiple dose administration in the fasted state for 10 days.

Pharmacokinetics in subpopulations

Age, gender, body weight and race

A population pharmacokinetic analysis from clinical studies with naldemedine did not identify a clinically meaningful effect of age, gender, body weight or race on the pharmacokinetics of naldemedine.

The pharmacokinetics of naldemedine in the paediatric population has not been studied.

Renal impairment

The pharmacokinetics of naldemedine after administration of a single 200 microgram dose of naldemedine was studied in subjects with mild, moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring haemodialysis, and compared with healthy subjects with normal renal function.

The pharmacokinetics of naldemedine between subjects with mild, moderate or severe renal impairment, or subjects with ESRD requiring hemodialysis and healthy subjects with normal renal function were similar.

Plasma concentrations of naldemedine in subjects with ESRD requiring dialysis were similar when naldemedine was administered either pre- or post-haemodialysis, indicating that naldemedine was not removed from the blood by haemodialysis.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of a single 200 microgram dose of naldemedine was studied in subjects with hepatic impairment classified as mild (Child-Pugh class A) or moderate (Child-Pugh class B) and compared with healthy subjects with normal hepatic function. The pharmacokinetics of naldemedine between subjects with mild or moderate hepatic impairment and healthy subjects with normal hepatic function were similar. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine was not evaluated.

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

In the rat fertility and early embryonic development study, prolongation of the dioestrous phase was observed at 10 mg/kg/day and above, but was not observed at 1 mg/kg/day (12 times the exposure [AUC_0-24hr] in humans at an oral dose of 200 micrograms). The effect on oestrous cycle is not considered clinically relevant at the proposed therapeutic dose. No adverse effects were observed in male or female fertility and reproductive performance at up to 1000 mg/kg/day (in excess of 16,000 times the exposure [AUC_0-24hr] in humans at an oral dose of 200 micrograms).

In the pre- and postnatal development study in rats, one dam died at parturition at 1000 mg/kg/day, and poor nursing, suppression of body weight gain and decrease in food consumption were noted at 30 and 1000 mg/kg/day. Decreases in the viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day and low body weights and delayed pinna unfolding were noted at 1000 mg/kg/day in pups. There was no adverse effect on pre- and postnatal development at 1 mg/kg/day (12 times the exposure [AUC_0-24hr] in humans at an oral dose of 200 micrograms).

Placental transfer of [carbonyl-¹⁴C]-naldemedine-derived radioactivity was observed in pregnant rats. [Carbonyl-¹⁴C]-naldemedine-derived radioactivity was excreted into milk in lactating rats.

In juvenile toxicity studies in rats, at the same dose levels, exposure in juvenile animals (PND 10) was increased compared to adult animals (2.3 to 7.4-fold). Novel histopathology findings were observed at all doses tested in female rats in ovaries (tertiary follicles/luteal cysts) in addition to irregular oestrous cycles, hyperplasia of mammary gland, and vaginal mucification already observed in adult animals (the lowest dose tested corresponded to an exposure margin of 6 or more, depending on the age of the pups). Three-day earlier vaginal opening indicative of an early onset of sexual maturity was also observed, but only at high exposures considered sufficiently in excess of the maximum human exposure at an oral dose of 200 micrograms.