Levodopa (LD) is the most effective treatment for managing the motor features of Parkinson's disease (PD)
; however, its benefits tend to decline over time, in part because of the development of motor complications that can be disabling for some patients. Patients with PD often lose “long-duration response,” a poorly understood process that allows antiparkinsonian effects to persist for longer than suggested by the pharmacokinetics (PK) profile of LD. 1 As the long-duration response becomes attenuated, patients with PD eventually become increasingly dependent on constant LD plasma levels to maintain control of motor symptoms. Furthermore, patients with PD experience variability in the dose-by-dose absorption and actions of LD. This variability can manifest as motor fluctuations as well as irregular control of the nonmotor aspects of PD. The most common patterns of motor fluctuations can be linked to the peripheral PK of LD. 2 As an 3 l-neutral amino acid, LD is absorbed exclusively by a facilitated transport mechanism in the proximal small intestine. Its uptake is subject to competition from other dietary amino acids, the bulk of food in the stomach and small intestine, local pH, bacterial overgrowth, and declining gastric motility as PD progresses.
After oral ingestion, LD can be rapidly absorbed, with the immediate-release carbidopa (CD)/LD formulation typically achieving peak plasma LD concentration (
C max) within 30 to 60 minutes. Because of the relatively rapid clearance of CD/LD (half-life: 1.5 hours), 3,4 many patients with PD experiencing motor fluctuations will notice a decline in symptom control within 3 to 4 hours after each oral dose. The therapeutic effects of LD exhibit a threshold for the onset of PD symptom relief at a plasma concentration of approximately 0.9 to 1.0 μg/mL. 5 Conversely, when plasma concentrations drop below this threshold, patients can experience “OFF” episodes. 6,7 Pharmacological strategies to enhance the consistency of suprathreshold LD plasma concentration can potentially result in reduced daily “OFF” time. 3,4
Because orally administered LD is subject to systemic conversion to dopamine, 1 of 2 peripherally acting inhibitors of
l-aromatic amino acid decarboxylase (AADC), CD or benserazide, is routinely combined with LD to block this process outside of the brain. Levodopa is also systemically converted by 8 O-methylation to the inactive metabolite 3- O-methyldopa (3-OMD), the concentration of which can exceed that of circulating LD. Drugs acting outside the blood-brain barrier to inhibit catechol- 9 O-methyltransferase (COMT) greatly decrease the creation of 3-OMD from circulating LD and enhance peripheral LD concentrations. The extensive systemic enzymatic conversion of LD to dopamine and 3-OMD explains why administration of LD alone requires several grams of daily intake for a sufficient quantity of the drug to enter the brain. 10 Inhibiting both AADC and COMT permits a greater fraction of an ingested LD dose to be available for exerting antiparkinsonian actions. 1
Two peripherally acting inhibitors of COMT, tolcapone and entacapone, were approved internationally in the 1990s for adjunctive use in patients with PD experiencing motor fluctuations.
Opicapone, the third 5-nitrocatechol COMT inhibitor to be developed, 11 was approved as follows: in Europe in 2016, 12 in South Korea in 2019, 13 and in the United States and Japan in 2020. 14 Opicapone differs from the 2 previously mentioned COMT inhibitors in that it requires only once-daily dosing due to its prolonged inhibition of COMT enzymatic activity. 15,16 After oral administration, opicapone rapidly inhibits the peripheral enzymatic activity of COMT through its high binding affinity ( 12 K d in subpicomolar range) and the formation of a reversible COMT-opicapone complex. The duration of COMT inhibition exceeds the short plasma clearance half-life of free opicapone, suggesting that the dissociation of the COMT-opicapone complex is relatively slow. 17 In 2 pivotal phase 3 studies, BIPARK-1 (NCT01568073) and BIPARK-2 (NCT01227655), once-daily treatment with opicapone 50 mg demonstrated a significant reduction in daily “OFF” time compared with placebo in PD patients experiencing motor fluctuations. 18,19 20,21
The objectives of this study were to assess the PK profile of opicapone 50 mg and the effect of once-daily opicapone 50 mg on soluble COMT (S-COMT) activity and LD concentrations in patients with PD taking CD/LD.
MATERIALS AND METHODS
This open-label phase 1 study (NCT03496870) was conducted at 3 sites in the United States. Participants were screened for a period of up to 27 days, after which eligible subjects were enrolled and admitted to the study center for baseline assessments (day −1). Screening was followed by a 15-day inpatient and outpatient treatment period with periodic sample collection for LD, 3-OMD, and opicapone PK and S-COMT activity. After the treatment period, there was a 4-day follow-up period with continuing periodic sample collection for opicapone PK and S-COMT activity (Supplementary Fig. S1,
). The protocol was approved by an institutional review board for each site and conducted in accordance with Good Clinical Practice guidelines, the US Code of Federal Regulations, and the Declaration of Helsinki. Written informed consent was obtained before any study-related procedures were conducted. https://links.lww.com/CNP/A25 Study Participants
The study included men and women, aged 18 to 85 years with a body mass index of 18 to 40 kg/m
2, who met the following criteria: clinical diagnosis of idiopathic PD for ≥3 years and improvement of PD motor symptoms from LD treatment; modified Hoehn and Yahr stage of ≤4 in the “OFF” state; ability to tolerate an overnight period of 12 hours without CD/LD; and a stable regimen of PD medications (including CD/LD) for ≥28 days before baseline.
Key exclusion criteria included the following: moderate or severe motor fluctuations (eg, that caused significant discomfort or impairment of function, were unpredictable, or required assistance from others), or severe or intolerable LD-induced dyskinesia; previous exposure to opicapone; a QT interval using Fridericia formula of >450 ms for men or >470 ms for women; clinically significant elevations in laboratory parameters; and any active, clinically significant unstable medical condition within 28 days before baseline.
Study Drug Dosing and Prohibited Medications
A summary of study drug dosing is presented in Supplementary Table S1,
. After screening, participants were admitted to the study center for baseline assessments (day −1) and were randomized to either CD/LD dosing at intervals of 3 hours (Q3H) or 4 hours (Q4H, days 1 and 2). On days 1 and 2, participants underwent PK and COMT activity blood sample collection after the first dose of immediate-release CD/LD (25/100 mg; 1 tablet) administered at about 07:00 https://links.lww.com/CNP/A25 a. m. Sampling continued for 2 subsequent doses (Q3H or Q4H based on randomization). At the study center, participants also received opicapone 50 mg at about 08:00 p. m. in the evenings of days 1 and 2. From days 3 to 12, patients self-administered (at home) opicapone 50 mg at about 08:00 p. m. From days 3 to 14, patients received their usual CD/LD regimen instead of Q3H or Q4H dosing. Participants were readmitted to the study center from days 13 to 15 for assessments and blood sample collection for LD, 3-OMD, and opicapone PK and S-COMT activity followed by 4 days of outpatient follow-up and blood sample collection for opicapone PK and S-COMT activity (days 16–19). On days 13 and 14, opicapone was administered at about 08:00 p. m.; the patients' usual CD/LD dosing was maintained. On day 15, CD/LD (25/100 mg, 1 tablet) was administered at about 07:00 a. m., followed by Q3H or Q4H dosing (same as days 1 and 2). For all opicapone treatment days (days 1–14), no food, liquids, or CD/LD doses were allowed within 1 hour of opicapone dosing (before or after). For the PK and COMT activity blood sampling days, the following restrictions applied: CD/LD was not to be taken after 07:00 p. m. and no food or liquids were allowed after 11:00 p. m. on days −1, 1, and 14 before blood sampling, and no food was allowed for 1 hour after each CD/LD dose.
Use of drugs in the following medication classes was prohibited within 28 days before baseline: any COMT inhibitor, apomorphine, dopaminergic receptor antagonist, vesicular monoamine transporter inhibitor, monoamine oxidase inhibitor (except selegiline or rasagiline), venlafaxine, desvenlafaxine, enzyme inducers, and continuous infusion of CD/LD.
Sampling Schedules and Bioanalytical Methods
Blood sample schedules for the determination of opicapone concentrations and S-COMT activity (days 1–2, 7, and 13–19) and LD and 3-OMD plasma concentrations (days 1 [without opicapone], 2, and 15) are shown in Supplementary Table S2,
Plasma samples were sent to Algorithme Pharma (Laval, Quebec, Canada) to assess opicapone, LD, and 3-OMD concentrations. The samples were analyzed using validated high-performance liquid chromatography with quadrupole mass spectrometry (LC-MS/MS) methods. For opicapone, quantification was conducted over a range of 10 to 2500 ng/mL; for LD and 3-OMD, the range was 25 to 5000 ng/mL. Concentrations were calculated using peak area ratios, and linearity of the calibration curve was determined using a least squares regression analysis. Erythrocyte samples were sent to Nuvisan GmbH (Neu-Ulm, Germany) for assessment of S-COMT activity using LC-MS/MS detection.
Analyses were conducted using the PK population, defined as all participants who received study drug, had ≥1 quantifiable postbaseline concentration for opicapone or LD, and had no major protocol deviations. Pharmacokinetics outcome parameters for opicapone included maximum plasma concentration (
C max), area under the plasma concentration versus time curve from 0 hours to last measurable concentration (AUC 0-tlast), time to maximum plasma concentration ( t max), and apparent terminal half-life ( t 1/2).
Plasma concentrations for LD and 3-OMD were determined for each of the first 3 CD/LD doses administered on days 1, 2, and 15 and summarized descriptively by dose regimen (Q3H or Q4H). All plasma concentrations below the lower limit of quantification were set to zero. Pharmacokinetics outcome parameters for LD included
C max, AUC 0-tlast, and t max. Minimum (“trough”) plasma concentration ( C trough) was also measured. Total AUC was approximated as the sum of the individual AUC intervals for each of the first 3 CD/LD doses on each PK sampling day. Fluctuation index (percentage peak-to-trough fluctuation), a measure of the consistency of medication exposure, was calculated as ([ C max − C trough] / C ave) × 100, with C ave defined as the average steady-state plasma concentration.
Pharmacokinetics parameters were calculated using noncompartmental methods and summarized using descriptive statistics, which included the mean, standard deviation (SD), and coefficient of variation. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for LD
C max, AUC 0-tlast, C trough, and fluctuation index. Geometric mean ratios were based on PK profiling for the last LD dose administered with opicapone (day 15) versus PK profiling for the last LD dose administered before opicapone (day 1), with comparison using an analysis of variance model for the log-transformed values. The model included a main effect for study visit only. Inhibition of S-COMT Activity
Soluble COMT activity was based on LC-MS/MS analyses of metanephrine, an enzymatic reaction product that results from the interaction of COMT with epinephrine. Soluble COMT activity was summarized descriptively as the percent of baseline activity ([
E i / E 0] × 100), with E i defined as the activity at each postbaseline time point and E 0 defined as the day 1 predose baseline activity. E max was defined as maximum S-COMT inhibition, with t E max defined as time to maximum inhibition. E ave was defined as the average S-COMT inhibition. Analyses were conducted using available data from the PK population, with no imputation of missing values. Safety and Tolerability
Safety assessments included vital signs (screening and days −1 to 2, 7, 15, and 19); physical examination (screening and days −1, 7, 14, and 19); electrocardiogram (screening and days −1, 2, 7, 15, and 19); clinical laboratory assessments (days −1, 7, 15, and 19); Columbia-Suicide Severity Rating Scale (days −1, 7, 14, and 19); and adverse event monitoring (throughout study).
Of the 17 participants who enrolled, 8 were randomized to receive CD/LD Q3H and 9 were randomized to Q4H. One participant randomized to Q3H was discontinued from the study because of a protocol deviation (ie, received a prohibited medication within 28 days before baseline). The PK population included the remaining 16 participants, all of whom were included in the analyses and completed the study. Key characteristics of these participants, as presented in
Table 1, were as follows: mean age (SD), 64.3 (9.5) years; PD disease duration, 6.1 (3.4) years; and daily LD intake, 529.4 (279.4) mg (corresponding to approximately 5.3 tablets of CD/LD 25/100 mg/d).
TABLE 1 -
Total (N = 16)
Age, mean (SD), y
Male, n (%)
White, n (%)
Asian, n (%)
Native Hawaiian/Pacific Islander, n (%)
Disease duration, mean (SD), y
Prestudy daily LD intake, mean (SD), mg
Concurrent use of other antiparkinsonian medications, n (%)
Drugs with dopaminergic pharmacological properties
Monoamine oxidase B inhibitor (selegiline or rasagiline)
Safety and Tolerability
No deaths, serious adverse events (AEs), severe AEs, or discontinuations due to AEs occurred during this study. Of the 16 subjects in the study, 8 (50%) experienced at least one treatment-emergent AE (TEAE) during the study. One patient reported a “moderate” TEAE of increased dyskinesia, which was considered related to study drug but resolved without changing study drug doses. All other TEAEs were considered “mild.” The most common TEAEs were puncture site bruise (n = 3), dizziness (n = 2), and headache (n = 2). There were no other clinically significant changes in clinical laboratory test results, vital signs, electrocardiograms, or Columbia-Suicide Severity Rating Scale results.
Opicapone mean plasma concentrations on day 1 (after the first study dose) were generally similar to those on day 14 (after the last study dose). On day 1 and day 14, mean
C max was 464.7 ± 457.7 and 459.2 ± 252.1 ng/mL, respectively; mean AUC 0-tlast was 1663.8 ± 1130.5 and 2021.6 ± 783.0 ng/mL·h, respectively. Values were also similar on day 1 and day 14 for t max (5.6 ± 3.5 and 4.7 ± 3.0 hours, respectively) and t 1/2 (1.2 ± 0.4 and 1.9 ± 0.6 hours, respectively). Inhibition of S-COMT Activity
After the first opicapone dose on day 1, S-COMT activity decreased compared with the predose time point, with an
E max of 74.6 ± 8.6% (or 25.4% of predose activity) achieved at 8.4 ± 3.1 hours ( t E max; Fig. 1). After 14 days of once-daily opicapone administration, E max was 84.0 ± 4.9%, with more than 65% S-COMT inhibition (<35% of predose activity) maintained for the entire 24-hour daily postdosing interval. After the last dose of opicapone on day 14, S-COMT activity gradually returned toward baseline values, although more than 35% inhibition was still observed on day 19 (end of follow-up period). FIGURE 1:
Mean S-COMT activity represented as a percentage of opicapone predose activity. Samples for S-COMT analyses were collected for 24 hours after administration of opicapone 50 mg at 08:00
p. m. on day 1 and for 120 hours after opicapone dosing on day 14 (ie, through end of follow-up on day 19). Levodopa Concentrations
On day 1 before the first opicapone dose, LD was rapidly absorbed and eliminated after each CD/LD dose. The addition of once-daily opicapone to CD/LD (Q3H or Q4H) resulted in higher mean LD plasma concentrations (
Table 2). Increases in LD concentrations were observed by day 2 after the first opicapone dose (administered approximately 11 hours before the first CD/LD morning dose; Table 2). On day 15, after 14 days of opicapone dosing (steady state), LD concentrations were higher at all time points as compared with day 1 before opicapone dosing ( Fig. 2). The differences between day 15 and day 1 were more pronounced after the last 2 daily CD/LD doses. The rate of decline in mean LD concentration was slower on day 15 than on day 1.
TABLE 2 -
Levodopa and 3-OMD Plasma Concentrations and Fluctuation Index After the Third Daily Dose of CD/LD 25/100 mg
Day 1: Before First Opicapone Dose
Day 2: After First Opicapone Dose
Day 15: After Last Opicapone Dose
CD/LD Q3H (n = 7)
CD/LD Q4H (n = 8)
CD/LD Q3H (n = 7)
CD/LD Q4H (n = 9)
CD/LD Q3H (n = 8)
CD/LD Q4H (n = 8)
max, mean (SD), ng/mL 1412.8 (654.2)
trough, ng/mL 546.8 (133.9)
0-tlast, mean (SD), ng/mL·h 2745.4 (943.3)
Mean (SD), ng/mL·h
Coefficient of variation, %
Mean (SD), %
Coefficient of variation, %
max, mean (SD), ng/mL 3730.2 (1537.1)
trough, mean (SD), ng/mL 3239.0 (1537.0)
0-tlast, mean (SD), ng/mL·h 10,308.9 (4641.3)
Mean (SD), ng/mL·h
Coefficient of variation, %
Mean (SD), %
Coefficient of variation, %
*Sum of the first 3 daily CD/LD doses.
†Day 15, Q4H (n = 9).
AUC, area under the concentration-time curve (from time 0 to last measurable time point or sum of the first 3 CD/LD doses).
Mean plasma LD concentrations. The first CD/LD 25/100 mg (single tablet) dose was at approximately 07:00
a. m. on days 1 and 15, with 3 subsequent doses (A) every 3 hours (Q3H) or (B) every 4 hours (Q4H). Opicapone 50 mg (single tablet) was administered at approximately 08:00 p. m. on day 14.
Total AUC (sum of LD AUC
0 -tlast from the 3 daily CD/LD doses) increased from day 1 to day 15 with Q3H dosing (from 7339 ± 2512 to 11,714 ± 4429 ng/mL·h) and Q4H dosing (from 7570 ± 2675 to 13,159 ± 4528 ng/mL·h). Levodopa C trough also increased after administration of once-daily opicapone ( Fig. 3), with GMRs indicating that these trough concentrations increased to a greater extent (95%–217%) than did peak concentrations (43%–44%; Supplementary Table S3, ). As a result, peak-to-trough fluctuation decreased by 32% to 45% with opicapone ( https://links.lww.com/CNP/A25 Fig. 3, Supplementary Table S3, ). Notably, https://links.lww.com/CNP/A25 C trough concentrations for Q4H LD dosing after opicapone on day 15 (749.1 ± 353.8 ng/mL) were similar compared with those of Q3H LD dosing before opicapone on day 1 (546.8 ± 133.9 ng/mL). At day 2, compared with day 1, coefficients of variation for peak-to-trough fluctuation index after the third LD dose decreased for Q3H dosing (day 1, 45.6%; day 2, 26.6%) but increased for Q4H dosing (day 1, 30.0%; day 2, 48.3%). At day 15, compared with day 1, coefficients of variation decreased for both Q3H (day 1, 45.6%; day 14, 39.6%) and Q4H dosing (day 1, 30.0%; day 15, 27.5%; Table 2). FIGURE 3:
Select LD PK parameters. (A) Levodopa trough concentration and (B) LD peak-to-trough fluctuation.
The addition of once-daily opicapone to CD/LD (Q3H or Q4H) resulted in lower mean 3-OMD plasma concentrations at day 15 (
Table 2). Total 3-OMD AUC decreased from day 1 to day 15 with Q3H dosing (27,848 ± 13,702 to 4590 ± 1841 ng/mL·h) and Q4H dosing (43,593 ± 14,918 to 9552 ± 7236 ng/mL·h). 3- O-methyldopa C max also decreased from day 1 to day 15 for both Q3H (3730 ± 1537 to 617 ± 235 ng/mL) and Q4H dosing (3961 ± 1384 to 671 ± 256 ng/mL), as did C trough (Q3H: 3240 ± 1537 to 504 ± 190 ng/mL; Q4H: 3397 ± 1227 to 554 ± 187 ng/mL). DISCUSSION
This study was conducted to further evaluate the PK of opicapone, its effects on LD plasma concentrations and the consistency of LD exposure (measured by peak-to-trough fluctuation index), and its effects on COMT inhibition. The study examined these outcomes in patients with PD who received once-daily opicapone 50 mg added to standardized regimens of CD/LD (the 25/100 mg immediate-release form commonly used in clinical practice) at 3- and 4-hour intervals. The results indicate that while opicapone was rapidly eliminated, the pharmacodynamic effect of opicapone on COMT inhibition after the first dose was prolonged beyond the established systemic clearance half-life of the drug. This observation is in keeping with earlier findings of rapid, marked, and extended inhibition of COMT due to the high binding affinity of opicapone
and the slow dissociation of the COMT-opicapone complex. 17 Catechol- 18,19 O-methyltransferase activity was reduced by almost 75% after a single dose of opicapone and maximally by 84% after multiple dosing to achieve steady state. Catechol- O-methyltransferase activity remained low over the entire 24-hour postdosing interval, and partial inhibition persisted for at least 5 days after repeat-dose administration of the drug was discontinued. The observed decrease in 3-OMD peak and trough concentrations after opicapone, as well as decreased total 3-OMD exposure, are also the expected outcomes of marked inhibition of COMT by 50 mg/d of opicapone. Together, these findings are supportive of once-daily opicapone dosing in patients with PD.
After administration of once-daily opicapone for 14 days, which would be expected to achieve steady-state effect, the peak plasma concentration of LD increased by an estimated 43% to 44%, while the trough concentration approximately doubled. Opicapone administration also increased the overall LD exposure (total AUC) for both CD/LD regimens (25/100 mg) by approximately 60% for Q3H dosing and 74% for Q4H dosing. Opicapone administration decreased 3-OMD peak and trough concentrations as well as overall 3-OMD exposure. Interestingly, 3-OMD concentrations generally exceeded LD concentrations before opicapone (day 1) as has been previously observed,
but LD concentrations exceeded those of 3-OMD after opicapone (day 15). These results also indicate that the addition of opicapone to CD/LD 25/100 mg doses elevated and extended suprathreshold LD concentrations (approximately 0.9–1.0 μg/mL), which can improve consistency of motor function in patients with PD experiencing episodic “OFF” time. 9 In addition, treatment with opicapone greatly reduced peak-to-trough variation in LD concentration. Suprathreshold LD exposure is a primary driver of symptom control. Notably, the addition of opicapone to Q4H dosing (day 15) achieved trough LD concentrations similar to those of Q3H dosing without opicapone (day 1), but with a reduced peak-to-trough fluctuation index. This finding suggests that opicapone may allow for less frequent LD administration while maintaining suprathreshold LD concentrations. 6,7 22
In a previous PK-pharmacodynamic study, once-daily opicapone was compared with entacapone 200 mg administered 3 times per day.
Another comparison was conducted in a randomized controlled clinical trial in which participants received entacapone with each LD dose. 23 These investigations demonstrated that opicapone 50 mg provided a greater increase in the bioavailability of LD as compared with entacapone. 20 In addition, opicapone 50 mg provided statistically significant reductions in “OFF” time and increases in “ON” time relative to placebo and was noninferior in terms of “OFF” time relative to entacapone. 23 No clinical comparison has been conducted between opicapone and tolcapone, a COMT inhibitor that is dosed 3 times per day and that requires monitoring because of rare instances of hepatic toxicity. 20 24
The findings of this study have implications for the real-world use of opicapone in the treatment of patients with PD who are experiencing “OFF” time. Opicapone has high binding affinity for COMT, resulting in marked and prolonged inhibition. The PK data show that COMT inhibition with opicapone resulted in a greater increase of trough LD concentrations than peak LD concentrations (found with both Q3H and Q4H dosing) resulting in a decreased peak-to-trough fluctuation index. An increase in the amount of time that LD concentrations remain above the threshold required for symptom relief is expected to be associated with reduction of “OFF” time. Opicapone also approximately doubled overall exposure to LD for both Q3H and Q4H dosing. Overall, the results of this PK study in PD patients using a marketed dose of opicapone were consistent with the effects seen in previous LD PK studies done in healthy volunteers.
In conclusion, this study showed that PD patients receiving once-daily opicapone 50 mg (a marketed dose in the United States and European Union) adjunctive to CD/LD can achieve and maintain enhanced plasma concentrations of LD for a longer duration than patients receiving immediate-release CD/LD alone. Because the net effect is a more prolonged LD concentration above the therapeutic threshold for controlling PD, these findings address a major unmet need in the treatment of PD: providing more consistent delivery of LD to the brain, which continues to be a challenge for optimizing treatment of PD. Enhanced COMT inhibition translates into one of the most promising ways to improve symptomatic control of motor fluctuations. Despite the obvious therapeutic advantage offered by more constant delivery of LD to the brain, achieving improved clinical outcomes in advanced PD may be a more complicated matter.
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