Methylnaltrexone

Methylnaltrexone is a selective μ-opioid receptor antagonist that has restricted ability to cross the blood-brain barrier, thus enabling reversal of opioid-induced peripheral effects, such as constipation, without affecting the central effects, such as pain relief. Treatment with subcutaneous methylnaltrexone 0.15–0.30 mg/kg, relative to placebo, significantly increased the rescue-free laxation response rate within 4 hours of the first dose (primary endpoint) in adult patients with opioid-induced constipation and advanced illness in two randomized, double-blind, placebo-controlled, multicentre, phase III studies; one was a single-dose study (n=154), the other a multiple-dose study (n= 133). In the multiple-dose study, rescue-free laxation response rates within 4 hours after at least two of the first four doses (coprimary endpoint) were also significantly higher in methylnaltrexone recipients than in placebo recipients. Moreover, median time to laxation after the first dose was significantly shorter in methylnaltrexone recipients than in placebo recipients in both studies. Methylnaltrexone was not associated with any significant changes in pain scores or central opioid withdrawal in these studies. Methylnaltrexone was generally well tolerated in clinical trials; most adverse events were of mild to moderate severity.


INTRODUCTION
Methylnaltrexone (Relistor; Wyeth Europe, Ltd., Maidenhead, United Kingdom) has been registered since 2008 for opioid-induced constipation in patients with advanced illness receiving palliative care, when response to laxatives has not been sufficient [1]. Opioid-induced constipation is a major clinical problem because 60%-90% of the patients who receive opioids for chronic pain management develop constipation [1]. Unlike other side effects, no tolerance to constipation is developed during chronic opioid use [2]. Laxative therapy is usually recommended, but may be burdensome and ineffective in some cases [3,4]. Methylnaltrexone may be effective in these cases [3]. A summary of the main characteristics of methylnaltrexone is given in Table 1.

CLINICAL USE
Methylnaltrexone (see Fig. 1) is available as a 12 mg/0.6 ml solution in a single-use vial for s.c. injection. The recommended dose is 8 mg every other day for a bodyweight of 38 -62 kg and 12 mg every other day for a bodyweight of 63-114 kg [1]. Patients whose bodyweight falls outside these ranges should receive 0.15 mg/kg every other day. Methylnaltrexone should not be dosed more frequently than once per 24 hours. Usage for Ͼ4 months has not been studied [2]. There is no indication that raising the dose increases the therapeutic response [4].

MECHANISM OF ACTION
Methylnaltrexone is a peripherally acting -receptor antagonist. Methylnaltrexone inhibits opioid binding at the -receptor without affecting the analgesic effects of opioids. The median inhibitory concentration of methylnaltrexone is 70 nmol/l [2, 5]. In the gastrointestinal tract, opioid-induced stimulation of the -receptors on enteric neurones reduces bowel movement, gastric emptying, and secretion of bowel fluids [6]. By antagonizing -receptors in the gastrointestinal tract, methylnaltrexone increases bowel movement and gastric emptying [2].

ANALYTICAL METHODOLOGY
The bioanalysis of methylnaltrexone in human plasma and urine can be executed by high-performance liquid chromatography with electrochemical detection [7].

PHARMACOKINETICS Absorption
After s.c. injection, methylnaltrexone is rapidly distributed in the body. Maximum plasma concentrations are reached 30 minutes after s.c. injection [8]. The s.c. pharmacokinet-ics are linear [1]. In vivo studies with oral administration of methylnaltrexone show that methylnaltrexone is slightly absorbed from the gut [1,8].

Protein Binding
The binding rate of methylnaltrexone to plasma proteins is 11%-15%. No relevant interactions at this level are to be expected.

Metabolism
A small portion of methylnaltrexone undergoes hepatic metabolism and methyl-6-naltrexol isomers and methylnaltrexone sulphate appear to be the main metabolites. No active metabolites of methylnaltrexone are observed in humans [2]. Although demethylation of methylnaltrexone to naltrexone occurs in rodents, no significant demethylation has been reported in humans [1,5].

Elimination
Eighty-five percent of methylnaltrexone is eliminated as unchanged drug, and it has a terminal half-life of 8 hours after s.c. injection [1]. Approximately 50% of methylnaltrexone is eliminated in the urine and a somewhat smaller portion is eliminated in the feces [2].

Drug Interactions
Because metabolism of methylnaltrexone is not a major elimination route, no relevant interactions with cytochrome P450 (CYP) activity-altering drugs are expected. Methylnaltrexone itself is a weak inhibiter of CYP2D6. A dose of 0.3 mg/kg of methylnaltrexone did not significantly inhibit the metabolism of a CYP2D6 substrate. CYP2D6 is mainly involved in the metabolism of antipsychotics and antidepressants.

Alterations with Disease or Age
According to the product information of methylnaltrexone, no significant influence of mild-to-moderate hepatic impairment has been reported. The effect of severe hepatic impairment has not been studied. In patients with mild-tomoderate renal impairment, no dose adjustments are required. In patients with severe renal impairment (creatinine clearance Ͻ30 ml/minute), it is advised to reduce the dose by 50%. Severe renal impairment reduced the renal clearance of methylnaltrexone eight-to ninefold. As a result of the lower renal clearance, the area under the plasma concentration-time curve of methylnaltrexone increased twofold. No relevant influence of age was observed. Because of the recent development of methylnaltrexone, the assessment of the influence of age and disease has been based on results obtained in a limited number of (unpublished) studies thus far.

PHARMACOGENETICS
For the most part, methylnaltrexone is not metabolized and no active metabolites are formed. Therefore, no relevant effects of genetic polymorphism on drug metabolism are to be expected.

PHARMACODYNAMICS
A dose-ranging study [4] showed the lack of a linear doseresponse relationship of methylnaltrexone in inducing a laxative response within 4 hours after administration in patients with no laxative response after stable laxative therapy. The optimal dose-response relationship was achieved at a dose of 0.

CONTRAINDICATIONS OR SPECIAL PRECAUTIONS
According to the product information, methylnaltrexone is contraindicated in patients with mechanical bowel obstruction. Methylnaltrexone should not be used during severe or persistent diarrhea. Application of methylnaltrexone during pregnancy or lactation has not been investigated. In patients with severe renal impairment (creatinine clearance Ͻ30 ml/ minute), dose adjustment to 50% of the standard dose is recommended.

PATIENT INSTRUCTIONS AND RECOMMENDATIONS FOR SUPPORTIVE CARE
Methylnaltrexone should be protected from light and stored at room temperature (20°C-25°C). Methylnaltrexone is used when needed, but not more frequently than one dose in a 24hour period. Methylnaltrexone should be discontinued when opioid therapy is stopped. During clinical trials, in one third of the patients a laxative response was reported within 30 minutes after s.c. administration of methylnaltrexone.