Metrifonate

Acetylcholinesterase (AChE) inhibitors are currently the most promising drugs available for the treatment of Alzheimer’s disease (AD). Their efficacy is based on the cholinergic hypothesis of AD which links reduced levels of cerebral acetylcholine (ACh) with declining cognitive function in affected individuals. AChE inhibitors are believed to work by increasing the level of ACh in the synaptic cleft by binding to local AChE and preventing the hydrolysis of ACh.

Metrifonate differs from other AChE inhibitors in that it is a prodrug which is non-enzymatically converted in vivo to the active moiety 2,2-dichlorovinyl dimethylphosphate (DDVP). DDVP administered alone has a very short plasma elimination half-life, but small amounts released from metrifonate are sufficient to inhibit AChE activity in vivo. DDVP is an irreversible inhibitor of AChE and activity is maintained for several weeks. Metrifonate has been used as an anthelmintic since 1962 and has been under investigation as a treatment for the symptoms of AD since 1990. Randomised, placebo-controlled clinical trials, using a variety of dose regimens, have demonstrated that metrifonate produces a significant, but modest, improvement in the 3 domains of AD: cognition, behaviour and function. However, it should be noted that with some assessment instruments in some trials, the ‘improvement’ was actually a reduction in the rate of worsening of symptoms compared with placebo. Weekly and daily schedules, with and without loading doses, have been evaluated and the research supports a fixed daily dose of 40 to 50mg, administered to supply approximately 0.65 mg/kg.

In studies of up to 6 months’ duration, metrifonate was well tolerated, and adverse events were mild and predominantly gastrointestinal. In clinical practice it is likely that metrifonate will be administered for several years and long term monitoring of adverse events will be important to further define the drug’s tolerability profile. Muscle weakness occurred in a dose-related fashion in ≈20 of 3000 patients taking part in long term trials, and in some patients respiratory support was required. The mechanism of muscle weakness is not well defined and requires further investigation.

Metrifonate is administered orally and after absorption is nonenzymatically converted to the active compound 2,2-dichlorovinyl dimethylphosphate (DDVP), at neutral or alkaline pH. After a short reversible phase, DDVP irreversibly binds to acetylcholinesterase (AChE). With the exception of nicotinic receptors, metrifonate does not bind to neurotransmitter receptors or binding sites associated with ion channels. Therefore, the pharmacological action of metrifonate is through inhibition of AChE and a consequent increase in levels of acetylcholine (ACh). Metrifonate also inhibits the activity of CNS butyrylcholinesterase (BChE) and AChE on red blood cells. This latter property has provided a useful marker for inhibition of brain AChE in humans. Metrifonate inhibits both the tetrameric and monomeric forms of AChE.

In healthy human volunteers, inhibition of AChE peaks at ≈1 hour after administration of metrifonate. Recovery of AChE activity is biphasic: most of the AChE activity is recovered after 8 hours, but the return to baseline activity takes several weeks and inhibition persists long after DDVP has been cleared from the blood. This persistence of activity allows consistent inhibition of AChE to be achieved within 7 to 8 days of initiation of metrifonate treatment with a loading dose. Without a loading dose it takes 6 to 8 weeks to establish a consistent AChE inhibition level.

Studies in rats have demonstrated the ability of metrifonate to improve memory in a manner independent of dose. However, a clear relationship between age, loss of cognitive function and metrifonate-induced improvement has not been established.

Metrifonate is a prodrug, thus the pharmacokinetics of its active metabolite DDVP are also important. In healthy volunteers the pharmacokinetics of a single dose of metrifonate 2.5 to 15 mg/kg were largely independent of dose. After a single oral dose of metrifonate ≈0.66 mg/kg, the blood concentration/time profiles of metrifonate and DDVP were similar, but the area under the blood concentration-time curve (AUC) of DDVP was 2% of that of metrifonate. Renal clearance of unchanged metrifonate and DDVP is negligible, suggesting rapid and complete metabolism. The bioavailability of metrifonate and DDVP were not significantly affected by concomitant food, or by the time of day the drug was administered.

In patients with Alzheimers’s disease (AD) treated with metrifonate 1.5 to 4.0 mg/kg for 6 days there was no marked difference in the AUC and peak blood concentration (C_max) values for metrifonate or DDVP on days 1 and 6, indicating that there was no accumulation of either compound. However, blood concentrations of both metrifonate and DDVP increased with dose. The time to maximum concentration and elimination half-life values were largely independent of dose for both compounds and unaffected by repeated administration of metrifonate. No pharmacokinetic studies of metrifonate in patients with AD at clinically relevant doses have been carried out.

Very little metrifonate or DDVP is excreted unchanged through the kidneys and the pharmacokinetics of the drug are generally unaffected by the renal status of patients.

All trials reported significant improvements (or in some instances a slowing of deterioration) in one or more of cognition, behaviour and function. In those trials that compared different doses of metrifonate, the changes were found to be dose related. All 5 trials reported a significant improvement in the cognitive subscale of the AD Assessment Scale (ADAS-cog), with the best improvement of 1.3 to 3.24 points versus placebo reported after 26 weeks of treatment using a variety of regimens. The trial which compared a no loading-with a loading-dose regimen suggested that using a loading dose was not advantageous in terms of efficacy, and may be associated with increased adverse events during the loading-dose period.

Most of the adverse events associated with metrifonate are attributable to peripheral cholinergic effects. These are common to all AChE inhibitors and are generally mild and transitory, with gastrointestinal events being the most common. Tolerability data have been collected from all the pivotal clinical trials of metrifonate in patients with AD, and from 1 small study (n = 39) specifically designed to evaluate safety and tolerability. In the latter, a loading dose of 2.5 mg/kg was used for 2 weeks followed by 1.0 mg/kg for 4 weeks. 76 and 80% of metrifonate and placebo recipients, respectively, experienced adverse events. During the loading-dose phase diarrhoea was the only event that occurred in metrifonate-patients at a frequency greater than 10% of that seen in the placebo group. During the entire 6-week study events occurring more frequently in metrifonate-treated than in placebo-treated patients were diarrhoea, nausea, leg cramps and accidental injury (falls). No severe adverse events were reported, but 1 patient discontinued therapy with metrifonate during the loading-dose phase because of adverse events.

Studies of 12 or 26 weeks’ duration reported the same range and severity of cholinergic adverse events. Again, these were generally mild, and in some trials it was not possible to differentiate between placebo and metrifonate recipients on the basis of overall adverse events. Abdominal pain, nausea, flatulence, diarrhoea and leg cramps were the most commonly reported events in disfavour of metrifonate. These occurred in fewer than 20% of patients (where the incidence was reported). In 1 long term noncomparative study (56 weeks) of metrifonate 15 to 17 mg/day (based on bodyweight) diarrhoea and abdominal pain were the only events that occurred at a rate ≥10%.

A pattern of more frequent and severe adverse events during the loading-dose compared with the maintenance-dose phase was seen in all trials which used such regimens. Laboratory indices were unaffected by metrifonate, but most trials reported a reduction in heart rate of 5 to 9 beats/minute. This was not considered clinically important.

Of concern is the report of muscle weakness in ≈20 of 3000 patients taking part in various long term studies of metrifonate in AD. A few of these patients required respiratory support. The cause of this adverse effect is not yet established.

Metrifonate is administered orally in tablet form. Loading- and no loading-dose schedules have been used, but it is likely that protocols based on the latter regimens would be recommended in clinical practice. The long-acting properties of metrifonate allow once daily administration, and dose is usually determined by bodyweight range rather than individual bodyweights. The dose used in the most recent clinical trials was between 40 and 50 mg/day which is ≈0.65 to 0.75 mg/kg/day.