No correlation between COMT genotype and entacapone benefi ts in Parkinson ’ s disease

Catechol-O-methyltransferase (COMT) inhibitors are used to increase the bioavailability of therapeutic L-dopa. We examined the effi cacy of entacapone in Parkinson’s disease patients who had daily “off” duration of ≤2 hours, and carried different COMT polymorphisms. A total of 168 PD patients were recruited from 19 centers. Subjects were administered with 100–200 mg of entacapone in combination with each dose of L-dopa for 2 months. The clinical effi cacy was evaluated based on the activities of daily living (ADL), score on the Unifi ed Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) stage, and Clinical Global Impression (CGI). COMT polymorphisms were genotyped. 3-O-methyldopa (3-OMD) levels were measured before and after the administration of entacapone. Entacapone administration produced signifi cant improvements in the total daily “on” duration, ADL, UPDRS score, and H&Y stage. Nineteen patients (11.3%) had the low-activity COMT genotype, 68 patients (40.5%) had the intermediate-activity COMT genotype, and 81patients (48.2%) had the high-activity COMT genotype. The effi cacy, and adverse effects of entacapone therapy did not differ between the three groups. There was a signifi cant reduction in 3-OMD, but this did not differ among the three genotypes. Entacapone provided an increased “on” duration and improved motor function in all COMT genotypes. Neurology Asia 2011; 16(3) : 211 – 216 Address correspondence to: Beom S. Jeon, Department of Neurology, Seoul National University, Seoul, 110-744, Korea. Tel: +82-2-2072-2876, FAX: +82-2-3672-7553, e-mail: brain@snu.ac. kr INTRODUCTION L-dopa is the most effective treatment for Parkinson’s disease (PD). However, side effects are associated with administered L-dopa being heavily decarboxylated into dopamine in the periphery. Therefore, peripherally acting dopa decarboxylase (DDC) inhibitors such as carbidopa or benserazide are combined with L-dopa to increase the bioavailability of L-dopa and reduce these side effects. When DDC inhibitors are used, 3-O-methylation of L-dopa becomes a signifi cant shunting pathway leading to 3-O-methyldopa (3-OMD) and thus reducing the bioavailability of L-dopa. Therefore, catechol-O-methyltransferase (COMT) inhibitors were developed to block the peripheral shunting of L-dopa and thereby increase the bioavailability and extend the halflife of L-dopa. Two COMT inhibitor compounds, tolcapone and entacapone, have been introduced into clinical Neurology Asia September 2011 212 usage, but the liver toxicity of tolcapone has made entacapone the most widely administered. The benefi ts of combining L-dopa/DDC inhibitor with entacapone have been confi rmed in several clinical studies, mainly in terms of reducing motor fl uctuations. The COMT gene in humans is localized to chromosome 22, band q11.2 and is polymorphic with a trimodal distribution of low (COMT), intermediate (COMT), and high (COMT) activities. This polymorphism, which is due to the alteration of a single encoded amino acid, leads to three to four fold differences in COMT activity in erythrocytes and other human tissues. The COMT genotypes could be expected to affect the response to COMT inhibitors, with high-activity COMT genotypes showing greater responses. Several studies have found that genetic polymorphisms signifi cant infl uence individual variations in the biotransformation of L-dopa. However, the results of other clinical studies were not consistent with predictions that a highactivity allele will produce greater benefi ts or more adverse events from COMT inhibitors. There may be several reasons for this discrepancy between the prediction and the observed responses. First, those studies were conducted in patients with “wearing-off” periods longer than 2 hours. Those patients were probably relatively advanced fl uctuators with severe dyskinesias, which may have made drug adjustment diffi cult. Second, only low numbers of each genotype were included. Therefore, the present study selected patients with wearing-off periods shorter than 2 hours, thereby hoping that they were in the earlier stage of parkinsonism than those in the previous studies and thus reducing the diffi culty of severe dyskinesia. We achieved a sample size of 168 by recruiting from 19 Korean centers. Since 3-OMD is a metabolite of L-dopa by COMT, and thus may refl ect the degree of COMT activity, preand post-treatment plasma levels of 3-OMD were measured to examine the correlations among the genotype, 3-OMD level, and the degree of benefi t of entacapone therapy.