Entacapone

The Parkinson's-Reversing Breakthrough

Alternative Treatment for Parkinsons

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Entacapone is readily absorbed across the intestinal mucosa and does not seem to be significantly affected by first-pass metabolism in the liver. The bioavailability of an oral dose of entacapone ranges from 30% to 46% (18,37-40). It is highly (98%) protein bound and metabolized via glucuronidation. Most reports place the elimination half-life of entacapone between 0.4 and 0.7 hours (18,37-39). Entacapone does not cross the blood-brain barrier to any significant extent and appears to exert its action exclusively in the periphery (41), although some inhibition of striatal COMT activity following entacapone administration in rats has been described (41,42). When administered to humans, the inhibition of COMT activity by entacapone is dose dependent. Soluble COMT is reduced by 82% with an entacapone dose of 800 mg, the maximum amount that has been administered (43). In multiple dose studies, 100 mg of entacapone, given four to six times daily with levodopa, reduced COMT activity by 25% compared to placebo, while 200 mg produced a 33% reduction and 400 mg generated a 32% diminution in COMT activity (38).

Entacapone also has a dose-related effect on both levodopa and 3-OMD phar-macokinetics. In the same group of patients noted earlier, the elimination half-life (T1/2) of levodopa was prolonged by 23%, 26%, and 48% at entacapone doses of 100, 200, and 400 mg, respectively, while the area under the levodopa plasma curve (AUC) was increased by 17%, 27%, and 37%, respectively (38). Investigators in two earlier studies, however, had noted a leveling off of the levodopa AUC increase between entacapone doses of 200 and 400 mg and suggested that this might be due to the interference in carbidopa absorption by entacapone at a higher dose (44,45). In other studies, utilizing an entacapone dose of 200 mg, increases in the levodopa AUC have ranged between 23% and 48% and prolongation of the levodopa T1/2 has been around 40% (18). Despite these rather dramatic alterations, no significant increase in the time to reach the maximum plasma levodopa concentration (T ) or the maximum plasma levodopa concentration itself (Cmax) is seen following the concomitant administration of levodopa and entacapone. The T remains between 30

max and 60 minutes (18,34,46-49). Nutt (50) notes that the absence of an effect on the levodopa T and C is true only for the initial dose of the day and that some modmax max est progressive elevation of the levodopa Cmax develops with repeated doses during the day. This does not carry over to the next day, however, and a progressive escalation of COMT inhibition does not occur (18,46). Concomitant with these changes in levodopa pharmacokinetics, entacapone also induces a significant reduction in the plasma AUC of 3-OMD, reflecting a reduced COMT-mediated peripheral metabolism of levodopa to 3-OMD (18,38,40). It was predicted that the clinical correlate of these pharmacokinetic alterations would be an extended efficacy of a levodopa dose, due to the combination of the prolonged T1/2 and an increased AUC of levodopa and the reduced AUC of 3-OMD, possibly without an increase in levodopa-related toxi-city in light of the absence of change in levodopa Cmax. Subsequent full-scale clinical trials have largely validated these predictions and confirmed the safety and efficacy of entacapone.

The Safety and Efficacy of Entacapone Study Assessing Wearing-Off (SEESAW) double-blind placebo-controlled trial, evaluated the safety and efficacy of entacapone over a six-month period in 205 PD patients on levodopa with motor fluctuations (51,52). A significant 5% increase in daily "on" time (approximately one hour) was documented in patients receiving entacapone, compared to the placebo group. Motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) (53), improved slightly in the entacapone-treated group, whereas it deteriorated in the placebo group during the six month trial. The average daily levodopa dosage diminished by 12% (from 791 to 700mg/day) in the entacapone-treated group, but did not change in the placebo group. Adverse effects were generally mild and manageable, consisting primarily of symptoms consistent with enhanced dopaminergic activity, such as dyskinesia, nausea, and dizziness. Dyskinesia was reported as an adverse effect by 53% (55/103) of patients on entacapone, compared to 32% (33/102) of individuals on placebo. Yellow/orange discoloration of the urine also occurred in 37% of those receiving entacapone, but diarrhea was infrequent (7%).

A second large multicenter study, the NOMECOMT study, had both a trial design very similar to the SEESAW study and very similar results (50,52,54). This trial (also six months in duration) included 171 PD patients on levodopa who were experiencing motor fluctuations. In the entacapone-treated group, the mean "on" time increased by 1.4 hours, compared to an increase of 0.2 hours in the placebo group. This relative increase of 13% in the treatment group was significant. Average daily levodopa dosage diminished by 12% in the entacapone group, compared to a 2% increase in the placebo group. Adverse effects in this study were similar to those in the SEESAW study, except that the worsening of dyskinesia was reported by only 8.2% of entacapone-treated participants (vs. 1.2% of those on placebo), whereas diarrhea was reported by 20%. An open-label three-year extension of this study demonstrated a sustained benefit of entacapone (55).

More recent studies have augmented the findings of the SEESAW and NOMECOMT studies. Two additional large multicenter trials have investigated the safety and efficacy of entacapone in PD patients (56,57). In an open-label study of eight weeks duration, 489 patients were administered entacapone in conjunction with each dose of levodopa up to a maximum of 10 doses/day (56). Some reduction in "off " time was experienced by approximately 41% of patients, and the quality of life, as measured by the PDQ-39, was also improved. In a double-blind study of 301 PD patients, most of whom were experiencing motor fluctuations, significant improvement in both motor function and activities of daily living was documented with entacapone compared to placebo (57). However, in another double-blind study, a trend toward improvement was noted but significance was not achieved (58). Concerns that the efficacy of entacapone might be reduced when used in conjunction with controlled-release levodopa preparations, because of a potential "mismatch" in absorption and metabolism of the two drugs, led several groups of investigators to address the issue (45,57,59-62). The effect of entacapone was, for the most part, found to be comparable between the standard and controlled-release levodopa preparations. Delaying entacapone administration until 30 or 90 minutes after lev-odopa administration did not produce any alteration in levodopa pharmacokinetics, compared with the concomitant administration (61).

In a study that compared rasagiline, entacapone, and placebo, both rasagi-line and entacapone reduced "off" time by similar amounts (1.18 and 1.20 hours, respectively) compared with a 0.4-hour reduction for placebo (63). A postmarketing surveillance study of 464 patients taking entacapone reported an approximate 57%

reduction in the mean "off" time. In this trial, diarrhea was the most frequently reported adverse event, occurring in approximately 8% of individuals (64). Two large open-label studies of 899 and 479 patients demonstrated improvement in both patient perception of quality of life and physician perception of global improvement (65,66). In another postmarketing report, Parashos et al. (67) found that in their clinical practice the most common reason for discontinuation of entacapone was not the adverse effects, but rather the lack of efficacy. Actual aggravation of parkinson-ism (worsening of symptoms) was the next most frequent reason for discontinuing the drug.

Although hepatic toxicity has primarily been associated with tolcapone, at least one report has described entacapone-induced hepatotoxicity (68). Excessive daytime sleepiness, including "sleep attacks," has also been described with entacapone (69).

Drug interactions are not a prominent problem with entacapone, although the capability of entacapone to chelate iron in the gastrointestinal tract has been noted (70), and it has been suggested that an interval of two to three hours be allowed between entacapone and iron ingestion (18). Although animal studies have suggested that COMT inhibition may increase apomorphine bioavailability (71), such an effect has not been demonstrated in humans, even when administering a double dose of 400 mg entacapone (72).

Levodopa may increase plasma homocysteine levels in individuals with PD (73-77). The clinical significance, if any, of this elevation is uncertain. Elevated homocysteine has been reported as a risk factor for vascular disease (78,79), dementia (80), and depression (81); but whether this holds true for the modest elevations of homo-cysteine seen in levodopa-treated PD patients is less clear. Entacapone is able to prevent the levodopa-induced rise in homocysteine (82,83)

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