Entacapone improves the availability of L-dopa in plasma by decreasing its peripheral metabolism independent of L-dopa/carbidopa dose

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1 Blackwell Science, LtdOxford, UKBJCPBritish Journal of Clinical Pharmacology36-525Blackwell Science, 2254Original ArticleEntacapone increases concentrations of L-dopaH. Heikkinen et al. Entacapone improves the availability of L-dopa in plasma by decreasing its peripheral metabolism independent of L-dopa/carbidopa dose Helena Heikkinen, Anu Varhe, Tarmo Laine, Jaakko Puttonen, 2 Marjo Kela, 2 Seppo Kaakkola 3 & Kari Reinikainen Orion Corporation, ORION PHARMA, Research Center, Espoo, 2 Orion Corporation, ORION PHARMA, Kuopio and 3 Helsinki University Central Hospital, Department of Neurology, Helsinki, Finland Aims Entacapone is a peripherally acting catechol-o-methyltransferase (COMT) inhibitor. To improve the benefits of oral L-dopa in the treatment of Parkinson s disease (PD), entacapone is administered as a 2 mg dose with each daily dose of L-dopa. This study evaluated the effects of entacapone 2 mg on the pharmacokinetics and metabolism of L-dopa given as standard release L-dopa/carbidopa. Methods Six different doses of L-dopa/carbidopa were investigated in this placebocontrolled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 4 6). Two different L-dopa/carbidopa doses were administered to each subject (5/ 2.5 mg and 5/37.5 mg, or / mg and /25 mg, or 2/5 mg and 25/ 25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L-dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(,2 h) of L-dopa to a similar extent at all doses of L-dopa/carbidopa, that is by about 3 4% compared with placebo (P <., 95% CI.5,.4). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C max values for L-dopa at all L-dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L-dopa were maintained for a longer period at all doses of L-dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-Omethyldopa (3-OMD) to about 55 6% of the placebo treatment level (P <., 95% CI -.72, -.35) and increased the mean AUC(,2 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) fold compared with placebo (P <., 95% CI.6,.). The mean AUC(,2 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65 75% of that observed with placebo (P <..5, 95% CI.76, -.) at each L-dopa/carbidopa dose except the 5/2.5 mg dose (P >.5, 95% CI.59,.5). The metabolic ratios (MR, AUC metabolite/auc L-dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD (P <., 95% CI -.85, -.68) and HVA (P <., 95% CI -., -.8) in plasma at each L-dopa/carbidopa dose, whereas the AUC DOPAC/AUC L-dopa ratio was increased again at all doses (P <., 95% CI.26,.9). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L-dopa/carbidopa affect the pharmacokinetics of entacapone. Correspondence: Helena Heikkinen, Research Centre, Orion Corporation ORION PHARMA, Orionintie, PO Box 65, FIN-2 Espoo, Finland. Tel.: ; Fax: ; helena.heikkinen@orionpharma.com Received 24 January 22, accepted 2 July Blackwell Science Ltd Br J Clin Pharmacol, 54,

2 H. Heikkinen et al. Conclusions The 2 mg dose of entacapone similarly and significantly increases the AUC of L-dopa by changing the metabolic balance of L-dopa independent of the L-dopa/carbidopa dose and therefore entacapone is likely to have a similar L-dopa potentiating effect independent of L-dopa dose. Keywords: 3-OMD, carbidopa, DOPAC, entacapone, HVA, L-dopa, pharmacokinetics Introduction Current treatment of Parkinson s disease (PD) involves inhibiting peripheral decarboxylation of oral L-dopa by coadministering a dopa decarboxylase inhibitor (DDC inhibitor) in a fixed combination with L-dopa. With a DDC inhibitor, the decarboxylation of L-dopa decreases and the metabolism shifts to the catechol-o-methyltransferase (COMT) pathway. Consequently, concentration of the product 3-O-methyldopa (3-OMD) increases in peripheral tissues and the degradation to 3-OMD becomes the main metabolic pathway when L-dopa is coadministered with a DDC inhibitor [ 3]. Entacapone is a specific, potent and reversible COMT inhibitor, with an apparent half-life of elimination of h after oral administration and.4 h after i.v. administration [4, 5]. As well as inhibiting the peripheral formation of 3-OMD, entacapone also affects the formation of the other metabolites of L-dopa, including that of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3- methoxy-4-hydroxy-phenylacetic acid (HVA) [6]. The short half-life of elimination and the reversible nature of COMT inhibition enables the safe coadministration of entacapone with each daily dose of L-dopa to increase the benefits of L-dopa therapy for PD [7 ]. It has been shown in earlier single dose studies in healthy volunteers that simultaneous administration of entacapone with L-dopa/carbidopa increases the AUC of L-dopa in a dose-dependent fashion by decreasing its peripheral metabolism [4]. It has been shown in PD patients that entacapone 2 mg significantly increases the availability of L-dopa in plasma when coadministered with varying doses of L-dopa and DDC inhibitor [7, 8, 3]. However, it has not been investigated whether the effects of this dose of entacapone on L-dopa pharmacokinetics and metabolism are dependent on the dose of L-dopa or DDC inhibitor. Standard-release tablets of L-dopa and carbidopa in fixed-dose combinations of / mg, 25/25 mg, 5/2.5 mg, and /25 mg are marketed for treatment of PD. In addition to these standard-release tablets, we included the higher 5/37.5 mg and 2/5 mg doses, also used in clinical practice, in the study design, and investigated the effects of entacapone 2 mg on the pharmacokinetics and metabolism of L-dopa over this range of doses. The pharmacokinetics of carbidopa and entacapone were also determined. Methods Subjects Forty-six Caucasian male volunteers with mean age (± s.d.) of 24 ± 3.4 years (range 8 35 years) and weighing 75 ± 6.8 kg (range kg) with body mass index of 23 ±.6 kg cm -2 (range 9 26 kg cm -2 ) were recruited. The subjects were healthy based on medical history, physical examination, ECG, and clinical laboratory tests and the absence of regular medication. The study protocol, the subject information text, and the consent form were approved by the Ethics Committee of the study centre. The purpose and the course of the study were explained to the subjects and written informed consent was obtained before inclusion in the study. Good Clinical Practice (GCP) Guidelines of the European Community and the Recommendations for Biomedical Research Involving Humans (Declaration of Helsinki of the World Medical Assembly and its amendments) were followed. One subject withdrew from the study for personal reasons. Study design This was a placebo-controlled, randomized, single-dose, four-way cross-over study that was double-blinded for entacapone and open for L-dopa/carbidopa. In addition to the four 24 h study visits, separated by a washout period of at least 3 weeks, the protocol included a screening visit and a poststudy visit. The subjects were divided into three groups of equal size (n = 4 6) in the order that they were enrolled in the study. Each subject was dosed with two different L-dopa/carbidopa doses (5/2.5 mg and 5/37.5 mg, or / mg and / 25 mg, or 2/5 mg and 25/25 mg). All doses consisted of standard-release L-dopa/carbidopa tablets as prescribed to PD patients (5/2.5 mg, /25 mg, / mg, and 25/25 mg). Each of the L-dopa/carbidopa doses were given on two consecutive visits at the same time as either entacapone (2 mg tablet, Orion Pharma, Blackwell Science Ltd Br J Clin Pharmacol, 54,

3 Entacapone increases concentrations of L-dopa Finland) or placebo, which was identical in appearance to the entacapone tablet, and in random order. The drugs were administered orally in the morning after an overnight fast of h during which only tap water was ingested. Tap water was not allowed for the hour prior to dosing of medication, which was given with 2 ml of water. Subjects remained ambulant, fasted and drank no liquids until lunch 4 h after dosing. Assessments Tolerability Adverse events were assessed by spontaneous reporting, inquiry and observation throughout the study. In addition, a physical examination was performed and blood pressure, heart rate and ECG were recorded and clinical laboratory parameters were measured at screening and post study visits. Adverse events were tabulated in system organ classes according to the WHO adverse event dictionary. The frequency, severity and causality to study treatment were evaluated descriptively. Clinical laboratory values were evaluated descriptively and paying special attention to values outside the reference range provided by the analysing laboratory. ECGs, blood pressure and heart rate were also evaluated descriptively. Blood sampling and drug analysis Serial blood samples of ml were collected via a catheter inserted into a forearm vein and transferred to tubes containing ethylenediaminetetraacetic acid. The samples were drawn before dosing and 5, 3, 45, 6, and 9 min and 2, 3, 4, 5, 6, 8,, 2, and 24 h after ingestion of study medication. The samples were kept on ice and plasma was separated by centrifugation at + 4 C, deepfrozen within.5 h of blood collection and stored at -7 C until analysis. An antioxidant, sodium metabisulfite, was added to the plasma samples for the determination of L-dopa, its metabolites and carbidopa before deep-freezing the samples. Plasma concentrations of these analytes were determined by ion-pair, reversed-phase high-performance liquid chromatography (RP-h.p.l.c.) with coulometric detection using a slightly modified previously published method [4]. The plasma used for the determination of entacapone was protected from light during the handling and storing procedures to avoid degradation of the analyte. Plasma concentrations of entacapone were determined by an RP-h.p.l.c. method with amperometric detection. The method was modified from the one published by Karlsson & Wikberg [5]. The limit of quantification was ng ml - for entacapone and 2 ng ml - for the other analytes. The intraassay coefficients of variation (CV) were lower than 5% and the interassay CVs lower than 9% for all the analytes at all concentrations. Evaluation Pharmacokinetics Standard noncompartmental methods were used to determine the pharmacokinetic parameters for L-dopa, 3- OMD, DOPAC, HVA, carbidopa, and entacapone based on the plasma concentration-time data. The maximum plasma concentration (C max ) and the time to maximum plasma concentration (t max ) were recorded directly from observed individual plasma concentrations. The area under the plasma concentration time-curve (AUC) was calculated by conventional linear-trapezoidal summation to time and extrapolation to infinity. The AUC for L- dopa was determined both from time 2 h and to infinity. As L-dopa concentrations were close to zero at 2 h after dosing at all six doses in most subjects, only the AUC(,2 h) is presented. The AUC(, ) was similar to AUC(,2 h). The AUC for 3-OMD was determined from 24 h, and for DOPAC, HVA, carbidopa and entacapone from 2 h for the same reasons as given for L-dopa. Statistical analysis The pharmacokinetic parameters for L-dopa, 3-OMD, DOPAC, HVA, carbidopa and entacapone were summarized using descriptive statistics. Metabolic ratios (MRs) were derived for each subject by dividing the AUC values of 3-OMD, HVA, and DOPAC by that of L-dopa. In addition, the ratio AUC HVA/AUC DOPAC was calculated. An analysis of variance (ANOVA) model appropriate for statistical analysis of cross-over designs was applied to AUC and C max values to test the differences between placebo and entacapone periods for each L-dopa/carbidopa dose. All values were log-transformed prior to analysis, which included sequence, period and treatment as fixed factors, and subject (sequence) and residual error as random effects. The model was applied for each of the three subject groups separately. Wilcoxon signed rank test was used to evaluate the differences in t max values between the entacapone and placebo periods for each L-dopa/ carbidopa dose. In all statistical evaluations, significance was concluded if the 95% confidence interval (95% CI) excluded. In addition, to describe further the effect of entacapone on the AUC and C max of L-dopa and its metabolites, the ratio of geometric means (entacapone vs placebo) with 95% CI was established for each of these parameters. Results Pharmacokinetics of L-dopa The pharmacokinetic parameters for L-dopa after six different doses of L-dopa/carbidopa taken with placebo or 22 Blackwell Science Ltd Br J Clin Pharmacol, 54,

4 H. Heikkinen et al. Table Pharmacokinetic parameters of L-dopa after administering of placebo or entacapone 2 mg with different doses of L-dopa/carbidopa. C max (mg ml - ) t max (h) AUC(,2 h)(mg ml - h) L-dopa/carbidopa dose (mg) Placebo Entacapone Placebo Entacapone Placebo Entacapone 5/ ± ±.2*.59 ±.4.94 ±.5.59 ±.2.76 ±.2 (-.4, -.2) (.5,.33) /.83 ±.26.7 ±.2.75 ± ±.56.2 ± ±.32 (-.29,.7) (.6,.35) /25.85 ±.3.72 ± ±.25.6 ±.59**.43 ± ±.35 (-.34,.2) (.2,.38) 5/ ±.66.9 ±.3**.58 ±.4.9 ± ± ±.8 (-.5, -.) (.5,.34) 2/5.32 ±.24.6 ±.2.79 ±.63.6 ±.68* 3.2 ± ±.72 (-.28,.4) (.24,.4) 25/25.76 ±.69.3 ±.23**.2 ± ±.58* 3.68 ± ±.94 (-.4, -.8) (.22,.38) Values are means with s.d.; 95% confidence intervals on the differences between the mean values for entacapone vs placebo are given in parentheses, n = 4 6. *P <.5, **P <., P <., ANOVA. Statistical significance was concluded if the 95% confidence interval excluded. entacapone are summarized in Table. L-dopa plasma concentration-time profiles are presented in Figure and the mean AUCs for L-dopa, 3-OMD, DOPAC, and HVA in Figure 2. Figure 3 shows the AUC and C max values of L-dopa and its metabolites as geometric mean ratios (entacapone vs placebo) with 95% CI. Entacapone increased the mean AUC(,2 h) of L-dopa by 3 4% with all six L-dopa/carbidopa doses (P <.). There was a decrease in the C max values of L-dopa (Figure 3), but this only attained statistical significance at three of the doses (Table ). Two or more peaks in the plasma concentration-time profile following single dose are frequently observed with L-dopa [, 2, 6, 7]. We also observed this phenomenon, which occurred with and without entacapone and was present at all doses, but especially at the two highest doses of L-dopa. At some doses (/25 mg, 2/5 mg and 25/25 mg) the time to peak concentration of L-dopa was significantly delayed by entacapone (Table ). However, at all doses, with or without entacapone, the initial phase of L-dopa absorption was rapid (Figure ). When given with entacapone, higher plasma concentrations of L-dopa were maintained for a longer period compared with placebo. Pharmacokinetics of 3-OMD, DOPAC and HVA Entacapone decreased the mean AUC(,24 h) of 3-OMD to 55 6% of that observed with placebo, a difference that was statistically significant at all L-dopa/carbidopa doses (P <., 95% CI -.72, -.35) (Figures 2 and 3). The plasma concentrations of DOPAC increased with all six L-dopa/carbidopa doses by fold following entacapone compared with placebo (P <., 95% CI.6,.) (Figures 2 and 3). Similarly, the AUC of HVA decreased following entacapone to 65 75% of the placebo treatment values (P <..5, 95% CI -.76, -.), except after the smallest dose of L-dopa, where the difference did not reach statistical significance (P >.5, 95% CI -. 59,.5) (Figures 2 and 3). Entacapone decreased the ratios of AUC 3-OMD/ AUC L-dopa (P <., 95% CI.85,.68), AUC HVA/AUC L-dopa (P <., 95% CI -., -.8) and it increased the ratio AUC DOPAC/AUC L-dopa (P <., 95% CI.26,.9). A significant decrease was also observed in the ratio of AUC HVA/AUC DOPAC (P <., -.68, -.84). Figure 4 displays the mean plasma concentration-time curves for 3-OMD, DOPAC, and HVA after administration of L-dopa/carbidopa 2/5 mg either with placebo or with entacapone 2 mg, which are representative of the other profiles. Pharmacokinetics of carbidopa and entacapone Table 2 summarizes the pharmacokinetic parameters of carbidopa during the placebo and entacapone phases. The latter did not statistically significantly affect the plasma concentrations of carbidopa at any of the L-dopa/ carbidopa doses. The pharmacokinetics of carbidopa showed considerable interindividual variation (Table 2). The pharmacokinetic parameters for entacapone are summarized in Table 3. The mean C max of entacapone was about. mg ml - at most of the L-dopa/carbidopa doses, although it was slightly lower at the two highest doses. The peak concentration of entacapone was reached at.8 to.2 h at the lower doses of L-dopa, increasing to.5 and.8 h at the two highest doses Blackwell Science Ltd Br J Clin Pharmacol, 54,

5 Entacapone increases concentrations of L-dopa.5 5/2.5 mg.8 / mg Placebo Entacapone /25 mg.4 5/37.5 mg Plasma L-dopa (mg ml ) /5 mg.8 25/25 mg Figure Plasma concentration profiles of L-dopa after administration of placebo or entacapone (2 mg) with six different doses of L-dopa/carbidopa. Data are presented as means with s.e. mean, n = 4 6. Time (h) Tolerability Adverse events reported following the different doses of L-dopa/carbidopa with and without entacapone were similar. Headache and nausea were the most common ones, in addition to respiratory disorders observed mainly during the post-study period. Nausea was more common with the high doses of L-dopa. Almost all the adverse events reported were mild or moderate. One serious adverse event was reported, but this was later assessed as unrelated to the study drug. Discussion Entacapone 2 mg increased the mean AUC of L-dopa significantly and consistently by 3 4% when it was given with six different doses of L-dopa/carbidopa. The increase in the amount of carbidopa from mg to 22 Blackwell Science Ltd Br J Clin Pharmacol, 54,

6 H. Heikkinen et al. 7 L-dopa 8 3-OMD 6 5 Placebo Entacapone AUC (,2 h)(mg ml h) /2.5 / /25 5/37.5 2/5 25/25 DOPAC /2.5 / /25 5/37.5 2/5 25/25 HVA * NS ** * 5/2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 L-dopa/carbidopa dose (mg) Figure 2 Mean AUCs of L-dopa and its metabolites after six different doses of L-dopa/carbidopa administered concomitantly with placebo or entacapone (2 mg). Data are presented as means with s.e. mean, n = 4 6. ANOVA P <., **P <., *P <.5, NS not significant. Table 2 Pharmacokinetic parameters of carbidopa after administering of placebo or entacapone 2 mg with different doses of L-dopa/carbidopa. L-dopa/carbidopa dose (mg) C max (ng ml - ) t max (h) AUC(,2h) (ng ml - h) Placebo Entacapone Placebo Entacapone Placebo Entacapone 5/ ± 23 4 ± 9.9 ±. 2. ±.7 32 ± 92 2 ± 76 (-.22,.93) (-.37,.6) / 3 ± 8 33 ± ±.9 2. ±.6 95 ± 7 93 ± 66 (-.8,.9) (-.56,.97) /25 82 ± ± ± ± ± ± 6 (-.63, 46) (-.87,.67) 5/ ± 4 ± ± ± ± 7 55 ± 226 (-.63,.56) (-.7,.88) 2/5 26 ± ± ±. 2.9 ± ± ± 93 (-.4,.47) (-.49,.72) 25/25 54 ± ± ± ±. 229 ± 8 32 ± 5 (-.3,.85) (-.,.) Values are means with s.d., n = 4 6; 95% confidence intervals on the differences between the mean values for entacapone vs placebo are given in parentheses. There were no statistically significant differences between entacapone and placebo. Statistical significance was concluded if the 95% confidence interval excluded Blackwell Science Ltd Br J Clin Pharmacol, 54,

7 Entacapone increases concentrations of L-dopa L-dopa 3-OMD.6 AUC C max.6 AUC C max Cl 95%.8.6 Cl 95% /2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 L-dopa/carbidopa (mg) DOPAC HVA 3 AUC C max.6 AUC C max Cl 95%.5.5 Cl 95% /2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 5/2.5 / /25 5/37.5 2/5 25/25 L-dopa/carbidopa (mg) Figure 3 AUC and C max values for L-dopa, 3-OMD, HVA and DOPAC; the ratio of geometric means with 95% confidence interval (CI 95% ) after administration of six different doses of L-dopa/carbidopa concomitantly with entacapone 2 mg vs. the administration of the same L-dopa/carbidopa dose with placebo. Table 3 Pharmacokinetic parameters for entacapone (2 mg) after administration with different doses of L-dopa/carbidopa. L-dopa/carbidopa dose (mg) C max (mg/ml) t max (h) AUC (,last) (mg ml - h) 5/2.5.6 ±.37.2 ± ±.54 /.4 ±.56.2 ±.82.4 ±.42 /25.34 ±.82.8 ±.62.4 ±.35 5/37.5. ± ± ±.33 2/5.65 ± ±.44.4 ±.33 25/25.69 ± ± ±.4 Values are means with s.d., n = mg in the mg fixed-combination tablet of L-dopa improved the bioavailability of the latter. These data are in agreement with findings from a previous study [8]. Furthermore, the proportional increase in L-dopa AUC caused by entacapone tended to be somewhat more pronounced with the /25-mg dose. More efficient DDC inhibition at this dose probably explains this observation. The formation of 3-OMD is somewhat greater after the /25 mg dose than after the / mg dose. Consequently, the effects of entacapone are more pronounced after the /25 mg dose. It has been reported that another COMT inhibitor, tolcapone, increases the C max of L-dopa [9, 2, 2]. The data from the present study indicate clearly that simultaneous administration of entacapone decreased rather than increased the peak concentration (C max ) of L-dopa. A similar decrease in the C max of L-dopa has also been observed in PD patients after a day combined treatment with standard-release L-dopa/carbidopa 2/5 mg and entacapone 2 mg, but this did not occur with controlled release of L-dopa/carbidopa at the same dose []. This decrease in C max is clinically beneficial and together with the increased AUC of L-dopa, it will help 22 Blackwell Science Ltd Br J Clin Pharmacol, 54,

8 H. Heikkinen et al. Plasma concentration (mg ml ) OMD DOPAC Placebo Entacapone HVA Time (h) Figure 4 Plasma concentration-time profiles of 3-OMD, DOPAC and HVA after administration of entacapone (2 mg) or placebo with a L-dopa/carbidopa dose of 2/5 mg. Data are presented as means with s.e. mean, n = 4. in delivering more sustained plasma concentrations and lower the risk of dyskinesia at peak dose [22, 23]. The initial absorption of L-dopa was rapid both with and without entacapone and had no lag-phase. It is well established that there may be two or more peaks in the plasma concentration-time curve of L-dopa after a single oral dose [, 2, 6, 7]. In the present study, the highest C max occurred slightly later at some doses when coadministered with entacapone. A similar trend for a delay in the occurrence of L-dopa C max caused by entacapone has been reported in earlier studies performed in PD patients, which describe fluctuations in the time taken for the drug s effects to wear off, but no prolongation in the time for clinical response to the drug [, 24]. Thus, as the initial absorption phase of L-dopa was rapid both with and without entacapone and entacapone did not essentially change the pattern of L-Dopa absorption, the slight delay in the occurrence of L-dopa C max with some L-dopa doses can be considered clinically insignificant. Entacapone clearly affected the plasma concentrations of 3-OMD, DOPAC, and HVA. These changes were most evident during the first 3 5 h after drug administration i.e. during the period when COMT activity was most inhibited by entacapone [4]. Although entacapone primarily inhibits the peripheral degradation of L-dopa to 3-OMD, it also inhibits the metabolism of DOPAC to HVA as a second step in the metabolism of L-dopa [6]. Like L-dopa, carbidopa also exhibits substantial variability in its pharmacokinetics [25, 26]. Although the mean AUC of carbidopa in the presence of entacapone tended to increase at the three highest L-dopa doses, this was not statistically significant. The bioavailability of carbidopa, which also is a substrate for COMT in vitro [27], should theoretically be increased by entacapone, a COMT inhibitor. There was no major difference in the relative bioavailability of entacapone at any of the L-dopa/carbidopa doses. At the two highest doses the absorption phase of entacapone was somewhat prolonged. It has been speculated that entacapone can decrease the rate of stomach emptying [28]. If so, a similar delay in absorption should have occurred at all six L-dopa/carbidopa doses. Despite this observed variability in the absorption rate of entacapone, the changes in L-dopa pharmacokinetics and its metabolism to 3-OMD were comparable at all doses. Consequently, we believe that the apparent delay in the absorption of entacapone observed in this study at the two highest doses of L-dopa/carbidopa most likely reflects the variability in the pharmacokinetics of entacapone, but has no consequence for the clinical effects of entacapone. Our data suggest that entacapone increases the bioavailability of L-dopa at least partly through inhibition of COMT activity, in the upper part of the small intestine, which is known to be rich in the enzyme [29, 3]. Entacapone was well tolerated at all L-dopa/carbidopa doses. There was no difference in the occurrence of adverse events at any dose of L-dopa/carbidopa whether administered with or without entacapone. Headache and nausea were the most common adverse events during both entacapone and placebo periods. Nausea, a known adverse effect of L-dopa, was more common at the higher doses of L-dopa as expected. In conclusion, our data support the regimen of administering entacapone at a dose of 2 mg irrespective of the dose of L-dopa/carbidopa Blackwell Science Ltd Br J Clin Pharmacol, 54,

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