Movement Disorders Vol. 24, No. 9, 2009, pp. 1319–1324 2009 Movement Disorder Society
Pharmacokinetic-Pharmacodynamic Crossover Comparison of Two Levodopa Extension Strategies Peter A. LeWitt, MD,1* Danna Jennings, MD,2 Kelly E. Lyons, PhD,3 Rajesh Pahwa, MD,3 Adrian L. Rabinowicz, MD,4 James Wang, PhD,4 Maria Guarnieri, DPM,4 Jean P. Hubble, MD,4 and Harold Murck, MD4 1
Departments of Neurology, Henry Ford Hospital and Wayne State University School of Medicine, Detroit, Michigan, USA 2 The Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA 3 Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA 4 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
Abstract: Controlled-release carbidopa and levodopa (CL-CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L-dopa) effects. In a randomized, open-label crossover study of 17 PD subjects with wearing-off responses, we compared 8hour L-dopa pharmacokinetics (PK) and clinical effects after two doses of CL-CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near-equivalent mean L-dopa areaunder-the-concentration-curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL-CR, P 5 0.86). The mean hourly fluctuation index for L-dopa concentration was 235% for CLE and 196% for CL-CR (P 5 0.004). The mean maximal concentration for the first CLE dose was
1,926 6 760 ng/mL and for CL-CR, 1,840 6 889 (P 5 0.33). During the PK studies, the mean time that L-dopa concentration was ‡1,000 ng/mL for CLE was 291 6 88 minutes and for CL-CR, 306 6 86 (P 5 0.33). The mean percent-time in ‘‘off’’ state was 18% for CLE and 28% for CL-CR (P 5 0.017), ‘‘on state without dyskinesia’’ was 64% for CLE and 65% for CL-CR (P 5 0.803), and ‘‘on state with nontroublesome dyskinesia’’ was 18% for CLE and 7% for CL-CR (P 5 0.03). Despite less ‘‘off’’ time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability. 2009 Movement Disorder Society Key words: Parkinson’s disease; levodopa; entacapone; pharmacokinetics; pharmacodynamics; motor fluctuation
Despite the development of dopaminergic agonists with high potency for stimulating striatal dopamine receptors, the most valuable treatment for Parkinson’s disease (PD) is the amino acid precursor of dopamine, levodopa (L-dopa).1 L-dopa continues to be effective throughout the course of PD, though generally without the consistency of benefit initially experienced. When
used in an earlier stage of PD, anti-parkinsonian effect from a single dose of L-dopa can last more than 24 hours.2 However, by 2 years after the start of L-dopa therapy, the actions of each dose regularly wear off for up to one-half of patients with PD.3 The loss of consistent symptomatic control from L-dopa is a major challenge for the long-term management of PD.4
*Correspondence to: Dr. Peter A. LeWitt, Henry Ford Health Systems—Franklin Pointe Medical Center, 26400 WestTwelve Mile Road, Suite 115, Southfield, MI 48034. E-mail:
[email protected] Potential conflict of interest: Drs. LeWitt, Jennings, Lyons, and Pahwa: received contractual payments from Novartis Pharmaceutical Corporation for the conduct of this study through their respective institutions, and each have also received compensation for other activities with Novartis, including scientific advisory roles, sponsored clinical trials, and lectures; Dr. Rabinowicz: a former employee of Novartis Pharmaceutical Corporation, is currently with Bayer Health-
Care Pharmaceuticals, Wayne, NY; Dr. Hubble: a former employee of Novartis Pharmaceutical Corporation, is currently with Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; Drs. Guarnieri and Wang: are employees of Novartis Pharmaceutical Corporation; Dr. Murck: is a former employee of Novartis Pharmaceutical Corporation, and is currently with Bristol-Myers Squibb Company, Plainsboro, NJ. Received 28 September 2008; Revised 26 October 2008; Accepted 11 March 2009 Published online 1 May 2009 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22587
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Wearing off between doses can be conceptualized as a decline in a mechanism that, early in the course of Ldopa-treated PD, behaves as if the drug’s anti-parkinsonian effect can be stored and released long after the rapid synthesis and catabolism of dopamine (which has a turnover of 15 minutes in the mammalian brain5). When patients with PD experience wearing off between L-dopa doses, this short-duration response (SDR) occurs in parallel to the drug’s peripheral pharmacokinetic (PK) profile.4,6 With the evolution of the SDR, the patient with PD has reached a therapeutic milestone at which improving consistency in circulating L-dopa concentration becomes the major factor for improving anti-parkinsonian control. To extend L-dopa’s peripheral PK profile, one pharmacological strategy has been to slow the release of 7,8 L-dopa in the upper GI tract. Another option is to lessen L-dopa’s diversion to an inactive metabolite, 3O-methyldopa (3-OMD). Catechol-O-methyltransferase (COMT), responsible for the peripheral conversion of L-dopa to 3-OMD, can be blocked by selective inhibitors of COMT, tolcapone and entacapone. Like sustained-release L-dopa, COMT inhibitors prolong the effects of each L-dopa dose so that patients affected with wearing off responses can experience extended clinical benefit.9 Both of these therapeutic strategies are commonly used, but there have been only limited comparisons of their relative effectiveness. In this study, we evaluated these treatment options in the same PD subjects using PK and clinical assessments after administering comparable L-dopa doses with the marketed branded products Sinemet CR 50-200 and Stalevo 150.
SUBJECTS AND METHODS Study Design This randomized, open-label, 2 3 2 crossover study was conducted at the Henry Ford Hospital Parkinson’s Disease and Movement Disorders Center (Southfield, MI), the Parkinson’s Disease and Movement Disorder Center at the University of Kansas Medical Center (Kansas City, KS), and the Institute for Neurodegenerative Disorders (New Haven, CT). The first patient was enrolled July 24, 2003, and the last on January 30, 2004. Subjects provided written informed consent approved by each center’s institutional review board. At enrollment, all subjects were managed with a stable daily regimen of carbidopa-L-dopa (with 300–600 mg/day of L-dopa) taken between 6 AM and 6 PM. L-dopa intake had been previously optimized for
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maximal clinical benefit despite dose-by-dose fluctuations. Other medications for PD (except for COMT inhibitors) were permissible as long as they were unchanged for at least 4 weeks prior to enrollment and throughout the study. Subjects who had a rating of more than ‘‘mild’’ dyskinesia or who were receiving dopamine-blocking medications were excluded from the study. Using a predetermined 1:1 ratio, subjects were randomized to one of two treatment sequences with either open-label carbidopa-L-dopa-entacapone (CLE) 37.5, 150, 200 mg, respectively (Stalevo 150; Orion Corporation, Espoo, Finland), followed by carbidopa-Ldopa controlled-release (CL-CR) 50, 200 mg, respectively (Sinemet CR 50-200; Merck & Co., Whitehouse Station, NJ), or else CL-CR followed by CLE. One CLE 150 tablet was selected to be the approximate equivalent of one CL-CR 50–200 tablet. This choice was based on PK studies of CL-CR 50–200 that showed bioavailability of its L-dopa content was 75% that of 7,8 L-dopa uptake from immediate-release forms. The bioavailability of L-dopa derived from CLE 150 is similar to immediate-release carbidopa-L-dopa (data on file, Novartis Pharmaceutical Corporation, East Hanover, NJ). Based on previous PK studies of COMT inhibition with entacapone,9 similar area-under-the-concentrationcurve (AUC) with CL-CR 50-200 and with CLE 150 was expected. With a reduction of daily L-dopa intake in the CLE dose by 25% when compared with L-dopa content in the CL-CR treatment arm, the investigators devised a t.i.d. dosing regimen based on each subject’s prestudy intake of L-dopa. Extra immediate-release CL (Sinemet 25-100) was allowed as needed during the study, except during the 12 hours prior to each PK assessment day. After randomization, subjects started their assigned treatment sequence. On Day 8 and 16 (1 week after initiation of the study medication), subjects returned to the clinic for an 8-hour visit without having taken the first morning dose of study medication (which was then administered at 8:00 AM, followed by a second dose at 12:00 noon). During clinic visits, subjects underwent repeated clinical assessments and blood draws for measurement of plasma L-dopa concentrations. A standardized breakfast with low fat and low protein content (fruit and toast) was consumed shortly before administration of study medication and a low protein-content lunch was provided 45 minutes after the second study medication dose. Other antiparkinsonian medications, such as amantadine and dopaminergic agonists, were continued unchanged in timing or dose.
COMPARISON OF SINEMET CR AND STALEVO Blood sampling by means of an indwelling intravenous catheter was conducted 60 minutes before the first L-dopa dose and at 15, 30, 60, 90, 120, 150, 180, 210, and 240 minute intervals after both the first and the second doses of the study drug. Specimens (1.2 mL) were placed in chilled heparinized tubes containing 25 lL of sodium metabisulfite solution (50 mg/ mL, in 0.1 N HCl), inverted several times, and then spun in a refrigerated centrifuge to separate plasma. Samples were immediately frozen on dry ice for batched assay of L-dopa by high-performance liquid chromatography HPLC. Assays were run in duplicate by NMS Labs (Willow Grove, PA) using a validated procedure. The lower limit of L-dopa measurement was 20.0 ng/mL. Subjects were assessed at baseline and the end of each treatment sequence with the Unified Parkinson’s Disease Rating Scale (UPDRS).10 At the same times, subjects provided information as to whether they had experienced, in the previous week, one or more of the following motor fluctuation patterns: none, wearingoff, unpredictable ‘‘off,’’ or ‘‘freezing’’ of gait. In addition, investigator- and subject-completed global assessments at the end of each treatment regimen evaluated the effectiveness of the treatment regimen at controlling Parkinsonism. During each 8-hour PK day, subjects underwent UPDRS Part III (motor examination) five times: 30 minutes before study drug administration and at 60 and 210 minutes after the first (8:00 AM) and second (12:00 noon) study medication dosing. Each UPDRS motor examination was performed and videotaped according to standardized guidelines. On a later occasion, one of the investigators (PAL, DJ, or RP) from a different clinical center reviewed the videotapes blindly and in randomized sequences. During the PK day at 30-minute intervals, subjects also completed a PD symptom diary for which they were asked to record whether they were ‘‘off’’ (experiencing re-emergence of parkinsonian signs and symptoms), ‘‘on’’ (achieving typical L-dopaenacted relief of Parkinsonism), ‘‘on with nontroublesome dyskinesia’’ (achieving typical relief of Parkinsonism together with nontroublesome involuntary movements), or ‘‘on with troublesome dyskinesia’’ (achieving typical relief of Parkinsonism together with troublesome involuntary movements). These ratings were in accordance with prior training of subjects by the study coordinator as to definitions and instructions for conducting such ratings in a standardized manner.11 At the end of the first PK day, subjects were provided with the second-period study medication to start the following day.
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Pharmacokinetic Analysis Assuming a similar variability for the same L-dopa preparation, a sample size of 16 completed subjects would be required to detect a P 5 0.05-level treatment difference at 90% power if the standard deviation of Ldopa concentration from its mean (SDc) during the 8hour assessment were to be 20.7% less with one of the L-dopa preparations. The planned outcome variables included the following PK metrics: (1) SDc; (2) time to achieve maximal L-dopa concentration after oral administration of the first (Tmax(0–4 hours)) and second dose (Tmax(4–8 hours)); (3) maximum L-dopa concentration observed (Cmax) during 4 hours after the first (Cmax(0–4 hours)) and second (Cmax(4–8 hours)) L-dopa doses; (4) AUC for plasma L-dopa, measured from the baseline blood draw through the 4-hour intervals after the 8 AM (AUC(0–4 hours)) and 12:00 noon (AUC(4– 8 hours)) L-dopa doses, calculated using the linear trapezoidal rule; (5) hourly fluctuation index (FI(0–8 hours)) during the 8-hour study, calculated in percent as the difference between the observed maximal (Cmax) and minimal (Cmin) L-dopa concentrations, divided by the total L-dopa AUC (AUC(0–8 hours)/8); and (6) amount of time during which L-dopa concentration exceeded 1,000 ng/mL (T>1,000 ng/mL), a value slightly greater than the median effective L-dopa concentration typically needed to maintain control of parkinsonian features.12 The PK comparisons between the treatments were determined in the context of an analysis of variance model (ANOVA) for the 2 3 2 crossover study design. The primary analysis was to compare SDc and T>1,000 ng/mL between CLE 150 and CL-CR 50/200. SDc and T>1,000 ng/mL were analyzed without log-transformation. Nonparametric procedures (such as the sign test) were used to compare the Cmax between treatments. All AUC and Cmax variables were analyzed separately, with log-transformation. The other PK parameters were analyzed without log-transformation. The comparison between study drugs was computed using the ‘‘ESTIMATE" statement of the SAS MIXED procedure. The test-reference contrast was constructed to obtain the P-value, the least squares mean, and the 90% confidence interval (CI) for the log-scale test-reference difference. The antilogs of least squares mean difference and its 90% CI constituted the ratio of sample geometric means and the 90% CI for the true test-reference ratio. Wilcoxon’s signed rank test was used to compare Tmax values between study drugs. When warranted, the analysis was performed for the doseadjusted AUC and Cmax values. A previous L-dopa PK
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P.A. LEWITT ET AL. TABLE 1. Demographics and baseline characteristics of subjects CLE 150 to CL-CR 50/200 sequence (n 5 8)
Characteristic
Sex (n) Male 6 Female 2 Mean (6SD) age (yr) 65.8 (9.1) Modified Hoehn and Yahr stage (n) Stage 2 (bilateral involvement) 6 Stage 2.5 (several backward steps without retropulsion) 1 Stage 3 (retropulsion) 0 Stage 4 1 Mean (6SD) UPDRS Part 2 (Activities of Daily Living 9.0 (5.1) section) total score Mean (6SD) daily levodopa dosage (mg) at baseline (and 443.8 (105.0) taken with carbidopa at a 4:1 ratio) Motor fluctuations experienced in addition to end-of-dose wearing off (n) Unpredictable ‘‘off’’ states (‘‘on-off’’) 4 Momentary immobility (‘‘freezing’’) 0
CL-CR 50/200 to CLE 150 sequence (n 5 9)
All subjects (n 5 17)
3 6 60.7 (8.8)
9 8 63.1 (9.1)
5 0 4 0 8.7 (3.9)
11 1 4 1 8.8 (4.4)
672.2 (301.2)
564.7 (253.0)
3 0
7 0
CLE, carbidopa 37.5/levodopa 150/entacapone 200 mg; CL-CR, sustained release carbidopa 50/levodopa 200 mg; SD: standard deviation; UPDRS: Unified Parkinson’s Disease Rating Scale.
study7 using CL-CR 50/200 found the mean deviation (percent of mean concentration) was 36.3%.
Analysis of Data Clinical efficacy outcome variables included patient PD symptom diary information, UPDRS scores, and global assessments by the investigators and subjects. Summary statistics were calculated by treatment for all efficacy variables. Continuous variables were summarized by sample size, mean, median, standard deviation, minimum, and maximum. Discrete variables were evaluated by frequencies and percentages. A subject’s percent time in a given motor state (derived from the symptom diary) was compared between the treatments using an ANOVA model for a 2 3 2 crossover design.
RESULTS Demographic and baseline characteristics of the 17 subjects are provided in Table 1. The mean (6S.D.) UPDRS Part 3 (motor section) total score, measured prior to the first morning dose of PD medication, was 20.1 (610.7). In addition to L-dopa, other anti-parkinsonian medications used included dopaminergic agonists (13 subjects), selegiline (3), amantadine (2), and trihexyphenidyl (2). Comparisons of PK parameters for CLE and CL-CR (Table 2 and Fig. 1) yielded statistically significant differences only for SDc and FI0–8 hours. For both variables, the CLE results exceeded those of CLCR. Mean L-dopa plasma concentrations for the CLE and CL-CR treatment arms did not differ significantly at any time point. The individual subject PK results for the two L-dopa formulations (Fig. 1A,B) illustrate their
TABLE 2. Pharmacokinetic analysis summary: mean values (6standard deviation) for two sequential doses of each levodopa formulation and their statistical comparisons Pharmacokinetic parameter (units) AUC(0–8 hr) (ng min/mL) SDc (ng/mL) T(>1,000 ng/mL) (min) FI(0–8 hr) (%) AUC(0–4 hr) (ng min/mL) Cmax (0–4 hr) (ng/mL) Tmax (0–4 hr) (min) AUC(4–8 hr) (ng min/mL) Cmax (4–8 hr) (ng/mL) Tmax (4–8 hr) (min)
CLE 150 639,490 42 291 235 230,392 1,926 122 409,099 3,063 321
(185,823) (7) (88) (35) (81,928) (760) (59) (123,656) (884) (32)
CL-CR 50/200 662,577 35 306 196 239,205 1,840 144 423,474 2,738 324
(277,739) (7) (86) (32) (138,561) (889) (61) (172,862) (1,173) (45)
P value 0.86 0.008 0.33 0.004 0.56 0.33 0.29 0.91 0.13 0.60
See Subjects and Methods text for definitions of terms. CLE, carbidopa 37.5/levodopa 150/entacapone 200 mg (Stalevo 150); CL-CR, sustained release carbidopa 50/levodopa 200 mg (Sinemet CR 50/200).
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COMPARISON OF SINEMET CR AND STALEVO
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showed no statistically significant differences between the two treatments at any of the postdosing time points (60, 210, 300, and 450 minutes). Comparisons between the CLE and CL-CR regimens with respect to the various patterns of motor fluctuations were not statistically significant. The investigator global impression of change indicated that 2 of 17 subjects were regarded as improved while receiving CLE, when compared with 4 of 17 regarded as improved while receiving CL-CR. Additionally, investigator assessment reported that 10 of 17 subjects worsened while receiving CLE, compared with 8 of 17 that worsened while receiving CL-CR. The other subjects were rated as unchanged. For self-assessments of change by subjects, the results were similar: 3 of 17 subjects reported improvement while receiving CLE and 4 of 17 with CL-CR; 10 of 17 reported worsening while receiving CLE and 8 of 17 with CL-CR. The other subjects rated themselves as unchanged. None of the assessments for global impression of change by either investigators or subjects showed statistically significant differences. Adverse Events
FIG. 1. Individual plasma levodopa concentration (ng/ml) in 17 subjects after administration of two doses at 4-hour intervals of (A) controlled-release carbidopa-levodopa (CL-CR; 50–200 mg) and (B) carbidopa-levodopa-entacapone 37.5–150–200 mg (CLE). (C) Mean plasma levodopa concentrations for the 17 subjects (6S.E.M.).
marked variability from the ‘‘idealized’’ appearance of graphs created from mean values (Fig. 1C). Despite similarities in most PK values with each study treatment, the CLE regimen was found to have less ‘‘off’’ time than CL-CR (18.3% versus 27.6%, P 5 0.017) and more ‘‘on time with nontroublesome dyskinesia’’ (17.5% versus 7.2%, P 5 0.031). These data came from the PD symptom diaries recorded by investigators during the two 8-hour PK days. There were no statistically significant differences in percentage of ‘‘on time without dyskinesia’’ (64% with CLE, 65% with CL-CR). Virtually no ‘‘on time with troublesome dyskinesia’’ occurred with either CLE or CL-CR. Total UPDRS scores were similar after the 1-week regimens of CLE and CL-CR. The blinded physician assessments of the videotaped UPDRS Part 3 (motor)
At least one adverse event considered to be related to study drug was reported by 47.1% of subjects while receiving CLE and by 35.3% while receiving CL-CR. The most common adverse event with both study drugs was dyskinesia (17.6% with CLE and 11.8% with CLCR). There were no serious adverse events reported, and no subjects discontinued study medication due to adverse events. Other adverse events reported were expected for the population studied in terms of age, chronic PD, and concomitant medical conditions. DISCUSSION In this comparison of two strategies to extend the anti-parkinsonian effects of L-dopa, we observed little difference in L-dopa PK findings between a sustainedrelease carbidopa-L-dopa preparation and a combination product containing the COMT inhibitor entacapone and immediate-release carbidopa-L-dopa. Although the L-dopa AUC values for the two formulations were similar, there was greater variability in L-dopa concentration for CLE than with CL-CR. Despite the pharmacokinetic similarities, the COMT-inhibitor formulation was associated with less ‘‘off’’ time and more ‘‘on’’ time with nontroublesome dyskinesia. The discrepancy between PK and pharmacodynamic findings is not easily explained but may be attributable to an under-powered comparison of clinical outcomes between the two treatment regimens. Although the mean Cmax for the 8 AM CLE treatment preceded the mean CL-CR Cmax by about 22
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minutes, this difference did not reach statistical significance. It should be noted that the study protocol involved a standardized light meal preceding the first L-dopa dose, which may have delayed the uptake of Ldopa. In this study, the gradual rise in plasma L-dopa concentration with CLE differed from results reported with the use of an immediate-release carbidopa-L-dopa preparation combined with a tablet of entacapone.13 A delayed L-dopa Cmax with coadministration of entacapone has also been observed in another study,14 but other investigations haven’t made this observation with either immediate-release9,15,16 or controlled-release Ldopa.17 A recent PK study with Stalevo 150 showed results similar to those of a CL-CR 50–200 mg preparation (Nacom retard) and to the PK findings reported here, although the rise of L-dopa plasma concentration from Stalevo 150 was somewhat more rapid and less sustained than from the CR-CL preparation.18 Our findings suggest that the combination CLE product (Stalevo 150) has a PK profile quite similar to that of CL-CR (Sinemet CR 50-200). One implication of these findings is that a patient’s first morning dose of CLE may benefit from coadministration of immediaterelease carbidopa-L-dopa to achieve a more rapid onset of anti-parkinsonian effect. The marked variability in plasma L-dopa concentrations resulting from both CLE and CL-CR administration (Fig. 1) emphasizes that neither product yields continuous dopaminergic stimulation throughout a dose cycle. With both products, the second dose later demonstrated a peak L-dopa concentration almost double that resulting from the first dose, indicating that dosing at 4-hour intervals may result in cumulative L-dopa effects L-dopa such as peak-effect dyskinesias and other drug-related adverse results. These findings emphasize the continuing need for an improved L-dopa formulation to achieve improved consistency of plasma concentration. Acknowledgments: This study was developed as an investigator-initiated research project by Dr. LeWitt in collaboration with Novartis Pharmaceutical Corporation. Pharmacokinetic analysis was performed by Art Straughn, PharmD (Drug Research Laboratory, University of Tennessee, Memphis, TN) under contract to Novartis Pharmaceutical Corporation. Author Roles: LeWitt contributed to study concept and design. LeWitt, Jennings, Lyons, and Pahwa contributed to the acquisition of data. LeWitt, Jennings, Lyons, Pahwa, Rabinowicz, Wang, Hubble, and Murck contributed to the drafting of the manuscript. Wang contributed to the biostatistical analysis. Rabinowicz, Wang, Guarnieri, Hubble, and Murck contributed to the administrative, technical, and material support. LeWitt, Rabinowicz, Hubble, and Murck contributed to the study supervision.
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