Methylnaltrexone

Methylnaltrexone bromide is a selective antagonist of opioid binding at the mu-receptor. In vitro studies have shown methylnaltrexone bromide to be a mu-opioid receptor antagonist (inhibition constant [K_i]=28 nM), with 8-fold less potency for kappa opioid receptors (K_i=230 nM) and much reduced affinity for delta opioid receptors.

As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier is restricted. This allows methylnaltrexone bromide to function as a peripherally acting mu-opioid antagonist in tissues such as the gastrointestinal tract, without impacting opioid-mediated analgesic effects on the central nervous system.

Absorption

Methylnaltrexone bromide is absorbed rapidly, with peak concentrations (C_max) achieved at approximately 0.5 hours following subcutaneous administration. The C_max and area under the plasma concentration-time curve (AUC) increase with dose increase from 0.15 mg/kg to 0.5 mg/kg in a dose-proportional manner. Absolute bioavailability of a 0.30 mg/kg subcutaneous dose versus a 0.30 mg/kg intravenous dose is 82%.

Distribution

Methylnaltrexone bromide undergoes moderate tissue distribution. The steady-state volume of distribution (Vss) is approximately 1.1 L/kg. Methylnaltrexone bromide is minimally bound to human plasma proteins (11.0% to 15.3%) as determined by equilibrium dialysis. Biotransformation Methylnaltrexone bromide is metabolised to a modest extent in humans based on the amount of methylnaltrexone bromide metabolites recovered from excreta. Conversion to methyl-6-naltrexol isomers and methylnaltrexone sulphate appears to be the primary pathway to metabolism. Each of the methyl-6-naltrexol isomers has somewhat less antagonist activity than parent compound, and a low exposure in plasma of approximately 8% of the drug-related materials. Methylnaltrexone sulphate is an inactive metabolite and present in plasma at a level of approximately 25% of drug related materials. N-demethylation of methylnaltrexone bromide to produce naltrexone is not significant, accounting for 0.06% of the administered dose.

Elimination

Methylnaltrexone bromide is eliminated primarily as the unchanged active substance. Approximately half of the dose is excreted in the urine and somewhat less in faeces. The terminal disposition half-life (t_1/2) is approximately 8 hours.

Special populations

Hepatic impairment

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexone bromide has been studied in 8 subjects each, with Child-Pugh Class A and B, compared to healthy subjects. Results showed no meaningful effect of hepatic impairment on the AUC or C_max of methylnaltrexone bromide. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone bromide has not been studied.

Renal impairment

In a study of volunteers with varying degrees of renal impairment receiving a single dose of 0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion of methylnaltrexone bromide. The renal clearance of methylnaltrexone bromide decreased with increasing severity of renal impairment. Severe renal impairment decreased the renal clearance of methylnaltrexone bromide by 8- to 9-fold; however, this resulted in only a 2-fold increase in total methylnaltrexone bromide exposure (AUC). C_max was not significantly changed. No studies were performed in patients with end-stage renal impairment requiring dialysis.

Paediatric population

No studies have been performed in the paediatric population.

Elderly population

In a study comparing single and multiple-dose pharmacokinetic profiles of intravenous methylnaltrexone bromide at a dose of 24 mg between healthy, young (18 to 45 years of age n=10) and elderly (65 years of age and over n=10) subjects, the effect of age on exposure to methylnaltrexone bromide was found to be minor. The mean steady-state C_max and AUC for the elderly were 545 ng/mL and 412 ng•h/mL, approximately 8.1% and 20%, respectively, greater than those for young subjects. Therefore, no dose adjustment is recommended based on age.

Gender

No meaningful gender differences have been observed.

Weight

An integrated analysis of pharmacokinetic data from healthy subjects indicated that methylnaltrexone bromide mg/kg dose-adjusted exposure increased as body weight increased. The mean methylnaltrexone bromide exposure at 0.15 mg/kg over a weight range of 38 to 114 kg was 179 (range=139-240) ng•h/mL. This exposure for the 0.15 mg/kg dose can be achieved with a weight-band-based dose adjustment using an 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg, yielding a mean exposure of 187 (range=148-220) ng•h/mL. In addition, the analysis showed that 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for body weight 62 to 114 kg correspond to mean doses of 0.16 (range=0.21-0.13) mg/kg and 0.16 (range=0.19-0.11) mg/kg, respectively, based on the body weight distribution of patients participating in studies 301 and 302.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Cardiac effects were observed in some non-clinical studies in canines (prolongation of action potentials in Purkinje fibers or prolongation of the QTc interval). The mechanism of this effect is unknown; however, the human cardiac potassium ion channel (hERG) appears not to be involved.

Subcutaneous injections of methylnaltrexone bromide at 150 mg/kg/day decreased fertility in rats. Doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did not affect fertility or general reproductive performance.

There was no evidence of teratogenicity in rats or rabbits. Subcutaneous injections of methylnaltrexone bromide at 150/100 mg/kg/day to rats resulted in decreased offspring weights; doses up to 25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) had no effect on labour, delivery, or offspring survival and growth.

Methylnaltrexone bromide is excreted via the milk of lactating rats.

Studies have been conducted in juvenile rats and dogs. Following intravenous injection of methylnaltrexone bromide, juvenile rats were found to be more sensitive than adult rats to methylnaltrexone-related toxicity. In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs (incidences of convulsions and labored breathing) occurred at dosages (≥3 mg/kg/day) and exposures (5.4 times the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg) that were lower than those that caused similar toxicity in adult rats (20 mg/kg/day). No adverse effects occurred in juvenile rats at 1 mg/kg/day or in adult rats at 5 mg/kg/day (1.6 times and 7.8 times, respectively, the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg).

Following intravenous injection of methylnaltrexone bromide for 13 weeks, similar methylnaltrexone related toxicity was observed in both juvenile and adult dogs. In adult and juvenile dogs given methylnaltrexone bromide at 20 mg/kg/day, clinical signs indicative of CNS toxicity and prolongation of QTc interval were observed. No adverse effects occurred in either juvenile or adult dogs at a dose of 5 mg/kg/day (44 times the exposure {AUC} in adult humans at a subcutaneous dose of 0.15 mg/kg).