Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer

Abstract

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson’s disease and end-of-dose deterioration in the response to levodopa (the “wearing-off” phenomenon). The drug indication is for Parkinson’s disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature.

Introduction

When levodopa (LD) was introduced for the treatment of Parkinson’s disease (PD) almost 40 years ago, it was first used intravenously (Birkmayer and Hornykiewicz, 1961), but soon thereafter, oral administration of high doses of several grams was introduced (Cozias et al., 1967; Barbeau, 1969; Hornykiewicz, 2001; Carlsson, 2002). LD was metabolized mainly by 2 enzymatic pathways: dopa decarboxylase (DDC) (Cozias et al., 1967) and catechol-O-methyltransferase (COMT) (Axelrod and Tomchick, 1958). The combination of DDC and LD markedly increased the bioavailability of LD. This also reduced the LD dose by up to 70%. However, there were considerable inter- and intraindividual variations in its absorption and pharmacokinetics (PK), which is reflected in the variability in motor response. The peak plasma LD concentration can vary up to 20-fold after an oral dose of LD.

Parkinson’s disease is an age-related disease affecting approximately 0.1% of the global population. The incidence of Parkinson’s disease is 0.8% between the ages of 60 and 69 years and 2.6% between the ages of 80 and 89 years. Although the most common form of the disease is idiopathic, possible risk factors include genetic predisposition, rural living, drinking well water, farming, industrial chemical exposure, and herbicide/pesticide exposure. Parkinson’s disease is a chronic, progressive neurodegenerative disorder characterized by abnormalities in the body’s ability to maintain normal motor control or posture and to execute purposeful movement. The most common type of Parkinson’s disease is idiopathic; it results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta, a midbrain structure that provides innervation to the striatum. Diagnosis is based entirely on clinical signs and symptoms. These symptoms usually do not occur until 70%–80% of the striatal dopaminergic neurons are lost. The cardinal features of Parkinson’s disease are tremor, bradykinesia, and an absence or decrease in spontaneous movement that includes mask-like faces, restricted arm swing, slowed gait, rigidity, and loss of postural reflexes (Delwaide et al., 1993; Gottwald, 1999).

CHEMISTRY AND PATHOPHYSIOLOGY

The oldest, most efficacious, and best tolerated drug for dopaminergic substitution therapy of patients with Parkinson’s disease is LD (Fahn et al., 2004). Comtan (entacapone) is available as tablets containing 200 mg. Entacapone is a selective and reversible inhibitor of COMT. It is indicated for the treatment of Parkinson’s disease as an adjunct to LD and carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29, as shown below:

Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites. When the decarboxylation of LD is prevented by carbidopa, COMT becomes the major metabolizing enzyme for LD, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD). Both LD and entacapone are rapidly absorbed and eliminated. Meals rich in large neutral amino acids may delay and reduce the absorption of LD. Entacapone has no antiparkinsonian activity as a sole agent. Therefore, it must be given as an adjunct to LD and a peripherally acting DDC inhibitor, such as carbidopa. Entacapone acts peripherally and does not penetrate the blood-brain barrier (BBB). The dose response shows that the maximum dose should be 200 mg. At a 400-mg single dose, the response is reduced.

When the enzyme DDC is blocked, the enzyme COMT compensates by degrading LD into 3-OMD in the periphery. Because entacapone does not have any inherent antiparkinsonian activity as a sole agent, it is being proposed to be used as adjunct to LD/DDC inhibitor therapy in the treatment of Parkinson’s disease. The proposed dose is one 200-mg tablet administered concomitantly with each LD/DDC inhibitor dose up to 10 times daily.

Entacapone is rapidly absorbed, with the plasma peak concentration occurring at approximately 1 hour or less, and has a bioavailability of approximately 35%. It is highly bound to plasma proteins (98%), mainly to albumin, and is almost entirely glucuronidated in the liver. It is eliminated mainly by the kidneys but also via the biliary route, and it undergoes enterohepatic circulation. The absorption of entacapone, like that of LD, is highly variable between different individuals and exhibits high intraindividual variability as well. It is poorly lipophilic and does not penetrate the BBB to any significant extent. Its clinical effects are thus due to peripheral COMT inhibition only (Nutt, 1998; Fahn et al, 2004).

The drug undergoes an isomerization step for conversion from trans isomer to cis isomer forms (Phase I reaction) prior to glucuronidation (Phase II conjugation reaction). This is the only active metabolite. The glucuronide metabolites of entacapone and cis isomer are eliminated in urine as glucuronide conjugates. The glucuronides account for 95% of all urinary metabolites (70% as parent and 25% as cis isomer glucuronides). The glucuronide conjugates of cis isomers are inactive. All drug interaction studies conducted in this new drug application (NDA) were related mainly to the pharmacodynamic (PC) interaction associated with those drugs that affect the CNS. These drugs are commonly administered for Parkinson’s disease. Few drugs are related to PK interactions.

CLINICAL PHARMACOLOGY AND REGULATORY VIEWPOINTS

This NDA was first submitted to the FDA by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999 (https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20796_Comtan_biopharmr.pdf). The drug indication is for Parkinson’s disease as adjunct therapy to LD/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone (COMT inhibitor).

It appears there is little or no relationship between entacapone and LD plasma levels. The LD Cmax occurs at the same time as entacapone Cmax. However, LD Cmax did not increase as entacapone doses increased from 50 mg to 400 mg. The extensive PK/pharmacodynamics analysis revealed that the relationship between entacapone Cmax and LD Cmax was unclear—a negative relationship in one study and concave in another (Troconiz et al., 1998). The plot of individual entacapone plasma concentrations and LD plasma concentrations at all doses, including placebo, was widely scattered in participants. In some situations, it was noted that LD plasma levels after placebo (i.e., LD/carbidopa and placebo) were higher than when LD/carbidopa were coadministered with entacapone. This raised some concern as to whether there is a real benefit to further increasing the entacapone dose.

The extensive data analysis suggests that there is no relationship between entacapone plasma levels and Unified Parkinson Disease Rating Scale (UPDRS) scores. From the PK/PD analysis, it was concluded that the maximum benefit, based on the lowest UPDRS scores, occurs at a LD plasma concentration of approximately 1000 ng/mL, which corresponds to an entacapone dose of 100 mg. Dyskinesia scores were at the time of entacapone and LD Cmax. This again corresponds well with the Cmax of entacapone and LD. However, considering all of the data, there is no clear relationship between dyskinesia scores and LD or entacapone plasma levels.

The main metabolic pathways of the catecholamines adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine were already known in the 1950s. The 2 major enzymes involved in their metabolism are monoamine oxidase and COMT (Axelrod and Tomchick, 1958). Entacapone increases the daily ON time by an average of 1 to 2 hours and correspondingly reduces the daily OFF time in patients with PD with motor fluctuations. The daily LD dose has been reduced by 10% to 30%. These positive effects are sustained in long-term use over several years (Gordin et al., 2004).

Because dopamine does not cross the BBB, it cannot be used as a drug for PD. An alternative approach is to use its prodrug, LD. When LD was initially introduced for the treatment of PD more than 40 years ago, it was administered intravenously, as mentioned earlier. The effect of this treatment was dramatic but short lived. Oral administration of LD was subsequently introduced, but high doses of several grams had to be given. This was effective but was associated with severe nausea and hypotension (Hornykiewicz, 2001; Carlsson, 2002).

The idea of using a COMT inhibitor was proposed in the 1950s, but no effective and safe substances were available at that time. Today, LD remains the most effective medication for PD; however, both immediate and long-term problems are connected with its use. The immediate problems include considerable inter- and intraindividual variations in its absorption and metabolism. The peak plasma concentration can vary up to 20-fold after an oral dose (Nutt et al., 1994; Watkins, 2000). Possible explanations for this include irregular gastric emptying, varying gastrointestinal motility, competition with neutral amino acids or their transporter in the gut (and BBB), and varying enzymatic metabolism.

At the time of the NDA approval process, the following comments were assessed by the safety and efficacy team of the FDA:

1. Overall, the sponsor has performed an extensive program to characterize the clinical pharmacology and PK of this drug.

2. There was no change in Cmax or Tmax of LD with dose. This is probably of clinical importance in that only the exposure is changed by increasing the dose. Some of the side effects, such as dyskinesia, are more associated with Cmax than area under-plasma concentration (AUC).

3. It appears that there is little or no separation between entacapone doses and some of the clinical responses, especially relative to the ON time data (Figure 1).

Figure 1.

Mean ON time (duration of clinical response, minutes) based on modified total motor score of UPFRS (levodopa test) after placebo or different doses of entacapone with an individual single oral dose of levodopa/DCI ([mean ± SD], n = 19). Reproduced with approximation the publicly available NDA.

The following observations are based on the limited data submitted to the FDA:

• In one study, the entacapone doses were placebo, 50 mg, 100 mg, 200 mg, and 400 mg. In this study, the 200-mg dose was found to produce the optimum ON time response.

• In the same study, there was no separation between doses in terms of modified total motor scores, as shown in Figure 2, and dyskinesia scores. However, in terms of recovery, the separation was more apparent at the 200- and 400-mg doses compared with placebo. In addition, there was noticeable separation between placebo of LD and 200 mg of entacapone (Figure 3).

• In another study, the 200-mg dose was selected for 4 weeks of treatment in patients. Overall, the total duration of ON time was approximately 30 minutes longer for Sinemet and entacapone compared with control (Sinemet alone) or placebo (LD/placebo; Figure 4).

• The mean Cmax of entacapone and LD, but not the AUC, was approximately comparable in elderly and young participants. No formal study has been conducted by the sponsor.

• In liver impairment patients, the Cmax and AUC were doubled compared with healthy participants. Dose adjustment by prolonging the dosing intervals in liver impairment patients is necessary and should be based on the individual patient. Further, LD/carbidopa were not administered in this study.

• A single dose was used in all special population studies and some of the drug interaction studies. Therefore, the effects after multiple doses of long-term therapy, especially in patients with liver impairment, are unknown. Thus, the data from these studies are of little clinical significance because entacapone must be given with LD/carbidopa, and the level of LD must be determined to establish the PK/PD in these populations

• All interaction studies focus mainly on the PD interactions with monoamine oxidase inhibitors. The only observed interaction is with isoprenaline.

• Entacapone PK appears to be linear (dose independent) at up to an 800-mg dose when coadministered with LD/carbidopa.

• It should be noted that this drug could be given up to 10 times daily. Thus, compliance is an issue in the elderly population, and this could be associated with safety and efficacy problems. It appears that there is little or no separation between entacapone doses and some of the clinical responses, especially relative to the ON time data (Figure 4).

Figure 2.

Mean UPDRS motor scores during the levodopa test after 4 weeks of adjunctive treatment with entacapone 200 mg or placebo in fluctuating parkinsonian patients receiving levodopa plus DDC inhibitor therapy (n = 23). Adapted with some modification from Gordin et al, 2004.

Figure 3.

The duration of motor response to levodopa (ON time in minutes, mean ± SD) based on total motor score of UPDRS during levodopa test after 2-week optimized levodopa treatment (control), after 4-week levodopa/placebo (placebo), and after 4-week levodopa/entacapone (entacapone) treatment in patients who started with entacapone (n = 23). Data are approximated from the publicly available NDA.

Figure 4.

Mean plasma levodopa levels after 4 weeks of adjunctive treatment with entacapone 200 mg or placebo in fluctuating parkinsonian patients receiving levodopa plus DDC inhibitor therapy (n = 23). Adapted with some modification from Gordin et al., 2004.

COMT is distributed throughout various organs, with the highest activities in the liver and kidney. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for LD, catalyzing the metabolism to 3-OMD in the brain and periphery.

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma PK of LD. When entacapone is given in conjunction with LD and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of LD are greater and more sustained than after the administration of LD and an aromatic amino acid decarboxylase inhibitor alone. It is believed that, at a given frequency of LD administration, these more sustained plasma levels of LD result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s disease. The higher LD levels also lead to increased LD adverse effects, sometimes requiring a decrease in the dose of LD.

CLINICAL PHARMACOLOGY STUDIES SUBMITTED BY THE SPONSOR

A total of 35 studies were conducted to evaluate the clinical pharmacology and PK of the LD/DDC/entacapone treatment regimen. These studies focus on the PK/PD of LD, 3-OMD, and entacapone.

Considering the inter- and intrasubject variability in the data and the assay, the AUCs of entacapone appear to be dose proportional for up to 800-mg single doses of entacapone with a fixed dose of LD/carbidopa. The Cmax of entacapone also appears to increase with the dose. The same trend was also seen for the entacapone metabolite Z-isomer. It should be noted that there was no evidence of accumulation after 10 days of multiple dosing. It is interesting to note that there was no change in the Cmax or Tmax of LD with dose. This is probably of clinical importance in that only the exposure (i.e., AUC) changes with the dose. It should also be noted that some of the side effects, such as dyskinesia, are more associated with Cmax and AUC. At doses >200 mg of entacapone, there was some disproportionate increase in the AUC of LD as the dose increased. Food does not appear to affect the absorption and bioavailability of entacapone.

When 200 mg of entacapone is administered together with LD and carbidopa, it increases the AUC of LD by approximately 35%, and the elimination half-life of LD is prolonged from 1.3 hours to 2.4 hours. In general, the average peak LD plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s disease patients suggest that the maximal effect occurs with 200 mg entacapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by entacapone when given with LD and carbidopa.

PK AND PHARMACODYNAMICS OF ENTACAPONE

Entacapone PK are linear over the dose range of 5 to 800 mg and are independent of LD and carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of approximately 0.6 hour, and the elimination half-life (β-phase) is approximately 2.5 hours. It was noted that after a single 200-mg dose of entacapone, the Cmax was approximately 1.2 µg/mL. It should be noted that the PK properties of LD and entacapone should be quite similar (Gordin et al., 2004). Also, when LD is administered in several frequent daily doses, the addition of entacapone reduces the daily fluctuations of plasma LD by 30% to 40% (Gordin et al., 2004).

Food does not affect the PK of entacapone. The volume of distribution of entacapone at steady state after i.v. injection is small (20 L). Entacapone does not distribute widely into tissues due to its high plasma protein binding. Based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 to 50 µg/mL. Thus, the plasma protein binding is dose and concentration independent.

Entacapone binds mainly to serum albumin. Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis isomer followed by direct glucuronidation of the parent and cis isomer; the glucuronide conjugate is inactive. After oral administration of a ¹⁴C-labeled dose of entacapone, 10% of the labeled parent and metabolite is excreted in urine and 90% in feces. Oral entacapone is rapidly absorbed in a dose-dependent manner, the plasma peak concentration occurring at approximately 1 hour (Keranen et al., 1994; Watkins, 2000). Entacapone is almost entirely glucuronidated in the liver. Entacapone is eliminated mainly by the kidneys, but also via the biliary route, and enters enterohepatic circulation. The absorption of entacapone, like that of LD, is highly variable. Entacapone is poorly lipophilic. Therefore, its clinical effects are due to peripheral COMT inhibition alone.

Because COMT inhibitors slow the elimination of LD, they prolong the half-life of LD and increase its bioavailability. A single dose of entacapone prolongs the half-life of LD by 25% to 75% and increases its AUC by 25% to 50% (Keranen et al., 1993; Myllyla et al., 1993; Kaakkola et al., 1994; Kaakkola, 2000; Merello et al., 1994; Nutt et al., 1994; Ruottinen and Rinne, 1996a, 1996b, 1996c; Gordin et al., 2003, 2004).

This phenomenon was seen especially clearly when LD was administered i.v., because its absorption was not influenced by its variable concentration (Nutt, 1998). The PK of LD during entacapone treatment are not influenced by the severity of PD, age of the patient, duration of LD therapy, or use of other antiparkinsonian drugs. By slowing the metabolism of LD, entacapone prolongs its elimination and increases its bioavailability. Entacapone does not affect the peak plasma LD concentration or the time to reach it after a single dose (Ruottinen and Rinne, 1996c; Nutt, 1998; Kaakkola, 2000). The PK of LD, or the effect of COMT inhibition, are not influenced by the severity of PD, duration of LD therapy, or age of the patient. The PK and PD effects of entacapone can be seen after the first dose and are sustained even in the long term (Merello et al., 1994; Ruottinen and Rinne, 1996a, 1996b, 1996c; Troconiz et al., 1998). When entacapone is administered together with LD frequently during the day, that is, in 4 to 5 daily doses or more, the mean daily LD concentrations are higher (Nutt et al., 1994), as the trough values increase more than the peak concentrations. As a result, the daily fluctuations in plasma LD are attenuated by 30% to 40% (Nutt et al., 1994). Even with frequent daily administrations of LD (up to 10 daily doses) with entacapone, there will be no accumulation of plasma LD from one day to the next. The effect of entacapone on the PK of LD has also been studied with controlled release LD preparations (Sinemet CR). Entacapone increases the bioavailability of LD by approximately 30% in single doses.

PK IN SPECIAL POPULATIONS

In special populations, entacapone PK are independent of age. No formal gender studies have been conducted. Racial representation in clinical studies was largely limited to Caucasians; therefore, no conclusions can be reached about the effect of Comtan on groups other than Caucasian. A single 200-mg dose of entacapone without LD and DDC inhibitor coadministration showed an approximately twofold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment compared with normal patients.

All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading, 7 patients with liver disease had mild hepatic impairment, and 3 patients had moderate hepatic impairment. A single oral 200-mg dose study was conducted in hepatic patients and healthy participants. In this study, there was an approximately 12-fold increase in the AUC and Cmax of entacapone and its Z-isomers in the liver impairment patients compared with normal. There was an increase in entacapone urinary excretion in liver impairment patients compared with heathy participants. Therefore, dose adjustment is necessary in patients with liver impairment. However, after a single 200-mg dose, the AUC of entacapone in patients with renal impairment did not differ from healthy participants. The drug is not eliminated renally, and therefore dose adjustment is not necessary with renal impairment. In elderly populations, there were no PK or PD differences compared with young ones.

As only approximately 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion for this drug. Consequently, entacapone should be administered with care to patients with biliary obstruction. The PK of entacapone have been investigated after a single 200-mg entacapone dose, without LD and DDC inhibitor coadministration, in a specific renal impairment study. There were 3 groups: normal participants, moderate impairment, and severe impairment. No important effects of renal function on the PK of entacapone were found. There were PK/PD relationships between entacapone and/or concentration and the plasma levels of LD, 3-OMD, and COMT. It appears that entacapone reduces the growth hormones by approximately 50% compared with the placebo.

Because the PK of LD and entacapone are quite similar, a combination tablet containing LD/carbidopa/entacapone (LCE; Stalevo) has been developed. The efficacy and safety are the same as when LD/carbidopa and entacapone are given as separate tablets. The use of this combination tablet fosters compliance and the proper use of entacapone and has gained wide acceptance.¹⁷

SYNOPSIS OF PHASE III CLINICAL STUDIES

Several randomized, placebo controlled, double-blind, adjunct entacapone studies have been reported for PD patients with motor fluctuations. Entacapone, 200 mg, was administered concomitantly with LD in 3 to 10 daily doses (mostly 4–6 doses). The daily ON time was increased significantly in all studies by 30 minutes to 2 hours in the entacapone compared with the placebo groups. There was a statistically significant difference between the groups in all these studies. The daily OFF time decreased correspondingly (Figures 5–8) (Rinne et al., 1998; Holm and Spencer, 1999; Gordin et al., 2004). The daily LD dose was reduced by 10% to 30%, mostly to reduce dyskinesias, in the entacapone-treated patients. The activities of daily living scores (Part II of the UPDRS) and motor scores (Part III of the UPDRS) were improved by up to 3 points in the entacapone compared with the placebo group. However, the benefit of entacapone was lost almost immediately after its withdrawal (Figures 5–8) Rinne et al., 1998; Holm and Spencer, 1999; Gordin et al., 2004). The ON and OFF times returned to baseline values, which is a strong indication of the efficacy of entacapone. The effectiveness of Comtan (entacapone) as an adjunct to LD in the treatment of Parkinson’s disease was established in three 24-week, multicenter, randomized, double-blind, placebo-controlled studies in patients with Parkinson’s disease.

Figure 5.

Mean change in duration of daily ON time, assessed from home diaries, during 6 months’ treatment with adjunctive entacapone or placebo in fluctuating parkinsonian patients receiving levodopa plus DDC inhibitor therapy. After withdrawals at 24 hours, the “ON Time” returned to zero (baseline). Adapted with some modification from Gordin et al., 2004.

Figure 8.

Effect of 24 weeks’ therapy with entacapone or placebo on the percentage of awake time spent ON assessed from patients’ home diaries in 205 patients with Parkinson’s disease and end-of-dose deterioration in response to levodopa. Entacapone 200 mg was given with each dose of levodopa/carbidopa (4–10 times daily) in this multi-center, double-blind randomized study. Patients spent a mean of 17 hours per day awake. Adapted from Holm and Spencer, 1999.

Figure 7.

Effect of 24 weeks’ therapy with entacapone or placebo on mean daily ON time assessed from patients’ home diaries in 171 patients with Parkinson’s disease and end-of-dose deterioration in response to levodopa. Entacapone 200 mg was given with each dose of levodopa/carbidopa or levodopa/benserazide (4–10 times daily) in this multi-center, double-blind randomized trial. Entacapone therapy was withdrawn for 2 weeks before the assessment at week 26. Adopted from Holm and Spencer, 1999.

Figure 6.

Mean change in duration of daily OFF time, assessed from home diaries, during 6 months’ treatment with adjunctive entacapone or placebo in fluctuating parkinsonian patients receiving levodopa plus DDC inhibitor therapy. After withdrawals at 24 hours, the OFF time returned to zero (baseline). Adapted with some modification from Gordin et al., 2004.

In 2 of these studies, patients had motor “fluctuations” characterized by documented periods of ON (periods of relatively good functioning) and OFF (periods of relatively poor functioning) despite optimum LD therapy. There was also a withdrawal period following 6 months of treatment. In the third study, patients were not required to have motor fluctuations. Prior to the controlled part of the studies, patients were stabilized on LD for 2 to 4 weeks. Comtan has not been systematically evaluated in patients who have Parkinson’s disease without motor fluctuations.

In the first 2 studies to be described, patients were randomized to receive placebo or entacapone, 200 mg, administered concomitantly with each dose of LD and carbidopa (up to 10 times daily but averaging 4–6 doses/d). The formal double-blind portion of both studies was 6 months long. Patients periodically recorded in home diaries the time spent in the ON and OFF states throughout the duration of the study. Effects of ON time did not differ by age, sex, weight, disease severity at baseline, LD dose, or concurrent treatment with dopamine agonists or selegiline. Abrupt withdrawal of entacapone, but without alteration of the dose of LD and carbidopa, resulted in a significant worsening of fluctuations compared with placebo.

Overall, there was little or no relationship between entacapone doses and the following clinical responses:

• ON time modified total score: Overall, the total duration of ON time was approximately 30 minutes longer at 200 and 400 mg compared with control (LD/carbidopa alone) and placebo (LD/carbidopa with placebo).

• Mean modified total motor scores: There was no separation between doses (Figures 5–8). However, the recovery appears to be slower at the 200- and 400-mg doses compared with placebo.

• Dyskinesia scores: Similar to motor scores, there was no separation between doses. However, the recovery was more rapid after placebo compared with 200- and 400-mg doses.

Several studies demonstrated that the daily ON time was increased significantly, by 30 minutes to 2 hours, with entacapone compared with placebo, and the OFF time decreased correspondingly (Ruottinen and Rinne, 1994; Poewe et al., 2002; Brooks et al., 2003). However, the benefit of entacapone was lost after its withdrawal in the studies (Figures 5–8). The daily LD dose was reduced by 10% to 30% in the entacapone group, whereas there was no change in the placebo. The LD dose had to be increased within days or weeks, especially in those patients in whom it had originally been reduced. Other secondary efficacy parameters were also evaluated in these studies, such as the total UPDRS scale. Furthermore, the daily OFF time also decreased more in the entacapone than in the placebo group (Gordin et al., 2004).

Entacapone slowed the elimination of LD from plasma and increased its AUC without affecting its Cmax or Tmax (Ruottinen and Rinne, 1996a, 1996b, 1996c). The high 3-OMD concentrations were effectively lowered by the 4-week entacapone treatment. The AUC of 3-OMD also decreased in patients whose daily LD intake was not reduced. Thus, the decrease in the 3-OMD concentration was mainly due to inhibition of O-methylation and not to lowered LD dose alone.

Accordingly, with the PK results, entacapone caused both a statistically and clinically significant increase in duration of motor response to each LD/DDC inhibitor dose without affecting the magnitude, onset, or peak latency of the motor response. Correspondingly, entacapone prolonged the duration of dyskinesia, but its magnitude and starting time remained virtually unaffected. The present increase in ON time was equal to that after a 200-mg dose of entacapone in the earlier double-blind, single-dose studies (34 minutes vs 35 minutes and 33 minutes) but lower compared with the ON time obtained in open studies (34 minutes vs approximately 1 hour) (Nutt et al., 1994; Merello et al., 1994; Schacht, 2016).

Entacapone was associated with significantly greater improvements in daily ON time than placebo at weeks 8, 16, and 24 (P < .005), as shown in Figures 7 and 8 (Holm and Spencer, 1999). However, the beneficial effects of entacapone are reversed rapidly after therapy withdrawal: 2 weeks after the withdrawal of entacapone, daily ON time significantly decreased and OFF time increased to values similar to those at baseline (Holm and Spencer, 1999).

RECENT UPDATE ON ENTACAPONE

Yi et al. (2018) showed the evidence for the efficacy, safety, and cost-effectiveness of LCE compared with LD/dopa-decarboxylase inhibitor (DDCI) for Parkinson’s disease (PD). There were 5693 records. Compared with LD-DDCI, LCI improved patient UPDRS II scores. The conclusion of the authors is that LCE can improve PD patients’ motor symptoms and daily living functioning compared with LD/DDCI. Also, they indicated that there are currently no definitive cures for PD. In the pooled analysis for phase III studies of 808 patients, entacapone demonstrated promising results in UPDRS II (P < .01) and III (P < .01) scores (Kuoppamäki et al., 2014).

The critical review by Schacht (2016) of the COMT Val158Met moderation of dopaminergic drug effects on cognitive function showed that 25 studies suggest that evidence for this pharmacogenetic effect is mixed for stimulants and COMT inhibiters, which have greater effects on D₁ receptors. However, evidence for this effect is strong for antipsychotics, which have greater effects on D₂ receptors. It was concluded that the COMT Val158Met genotype represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs. The author indicated that COMT inhibitors can improve the cognitive function the most among Val allele homozygotes, while antipsychotics improved it the most among Met allele homozygotes. In another study, it was suggested that the COMT Val158Met polymorphism could be an information biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD (Yamamoto et al., 2021).

Parkinson’s disease patients may require device-aided treatment to reduce the patient’s fluctuation stages. LD-carbidopa intestinal gel (LCIG) continuous infusion is a recognized option in clinics (Senek et al., 2017, 2020; Öthman et al., 2021). The drug-containing gel is infused directly into the small intestine (Senek et al., 2020).

Öthman et al (2021) successfully reported the first clinical experience of LD-entacapone-carbidopa intestinal gel (LECIG) therapy. LCIG is used in the treatment of motor fluctuations in PD (Wirdefeldt et al., 2016). However, there are limitations and concerns with LCIG therapy, such as the size, weight, and development of peripheral neuropathy (Nilsson et al., 1998; Nyholm et al., 2003, 2012a and b; Ceravolo et al., 2013). It was suggested that the product in the intestinal gel is lower in the amount of LD administration (Senek et al., 2017).

The combination of LCIG and the oral COMT inhibitor entacapone was tested (Nyholm et al., 2012a and b). This then led to the development of LECIG. However, one issue in this treatment was LD accumulation during the day (Ingman et al., 2012). This could be a problem with LECIG infusion according to the PK characteristics compared with those of LCIG (Senek et al., 2018). When switching from LCIG to LECIG, the results suggest that the continuous dose needs to be decreased by approximately 35% on a population level (Senek et al., 2020). Also, there has been a population PK study using microtubule administration. In this analysis, the authors state that PK/pharmacodynamics will be used to individualize dose selection (Senek et al., 2018) and utilize flexibility offered by the microtubules.

COMT was first identified by the biochemist Julius Axelrod in 1957. COMT inhibitors such as entacapone save LD from COMT and prolong the action of LD (Ruottinen and Rinne, 1998). The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The best studied is Val158Met (Corvol et al., 2011; Schacht, 2016). Others are rs737865 and rs165599, which have been studied, for example, for association with personality traits, response to antidepressant medications, and psychosis risk associated with Alzheimer’s disease.

More recent data are not presented, such as the potential utility of adding entacapone to the LD/carbidopa association in subsets of Parkinsonian patients, for example, those carrying variations in the gene encoding for the enzyme COMT or those with sleep disturbances. The overview does not mention the gel formulations that include entacapone, developed for patients with advanced Parkinson’s disease who do not achieve sufficient stability in symptom relief with oral treatment. Thus, the review should be extended with the inclusion of relatively recent acquisitions on entacapone. Moreover, the manuscript is not well organized, and similar information is provided in different sections. The text should be thoroughly revised to offer a rational presentation of the different relevant aspects of entacapone clinical pharmacology and use. In terms of PK/PD, repeat administration of heterozygous patients remains to be determined (Corvol et al., 2011). In patients with stable PD who do not experience motor complication, it provides no measurable improvement in UPDRS scores. However, it does improve secondary measures of quality of life (Olanow et al., 2004).

CONCLUSION

LD is the most effective treatment for Parkinson’s disease, though this therapy is often associated with a fluctuating response. Entacapone is a potent, specific, and reversible COMT inhibitor. The drug has been shown to act peripherally, but not centrally, when given at clinically effective doses. The AUC and half-life of LD are increased after entacapone administration, whereas Cmax and Tmax are generally not affected. Entacapone was shown to be effective for the treatment of patients with Parkinson’s disease experiencing the “wearing-off” phenomenon. Daily ON time was increased by 1 to 1.2 hours with 6 months’ entacapone therapy compared with placebo, and in one trial, daily OFF time was decreased by 1.2 hours vs placebo. Entacapone also reduced the mean daily LD dosage compared with placebo. The most common adverse events of COMT inhibitors are dopaminergic events; dyskinesia, nausea, diarrhea, constipation, abdominal pain, and urine discoloration were among the most common adverse events with entacapone in studies of 6 to 12 months’ duration. Thus, entacapone is a potent, specific, orally acting COMT inhibitor that can be administered simultaneously with each dose of patients’ LD/DDC inhibitor (e.g., carbidopa).

Disclaimer

The information in this paper represents the author’s opinion and in no way represents the current regulatory policies and/or standards of the Center for Drug Evaluation and Research, the Food and Drug Administration (FDA), or the Department of Health and Human Services.

Interest Statement

None.