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Parkinson disease
Review of RYTARY (carbidopa and levodopa) clinical efficacy
and safety
Rohit Dhall, MD
David L. Kreitzman, MD
Correspondence to
Dr. Dhall:
drdhall@gmail.com
ABSTRACT
Parkinson disease (PD) is a slowly progressive, incurable, neurodegenerative disorder with progressive
motor symptoms that can be managed with treatments. Levodopa is generally recognized as the most
effective and widely used treatment for PD. It improves function and quality of life, morbidity, and mortality, and therefore reduces individual and societal costs. Levodopa has a relatively short half-life, however, and is quickly metabolized in the plasma, leading to fluctuations, including wearing-off of effect
and inconsistent symptomatic relief as well as development of dyskinesias, with both wearing off and
dyskinesias worsening with advancing disease. Immediate-release and controlled-release formulations
have been used with success, but motor fluctuations remain a problem. RYTARY (levodopa and carbidopa, IPX066) is an oral extended-release therapy composed of carbidopalevodopa microbeads
designed to dissolve at various rates that allows for quick absorption and sustained levodopa release
over an extended period. In development studies, RYTARY improved symptoms in patients with both
early and advanced PD and offered significantly improved Unified Parkinson Disease Rating Scale
scores and on times, without worsening troublesome dyskinesias when compared to other levodopa
formulations. Tolerability and safety were comparable to other formulations. This section reviews the
data that support the use of RYTARY in the treatment of PD. Neurology 2016;86 (Suppl 1):S13S24
GLOSSARY
ADVANCE-PD 5 A Study to Evaluate the Safety and Efficacy of IPX066 in Advanced Parkinsons Disease; AE 5 adverse
event; APEX-PD 5 A Study to Evaluate the Safety and Efficacy of IPX066 in Subjects with Parkinsons Disease; ASCENDPD 5 Comparison of IPX066, a Novel Carbidopa-Levodopa Extended-Release Formulation, and CD-LD-Entacapone in
Advanced Parkinsons Disease; CD 5 carbidopa; CGI-C 5 Clinician Global Impression of Change; CLE 5 carbidopa-levodopa
1 entacapone; CR 5 controlled release; DDC 5 dopa decarboxylase; EQ-5D 5 EuroQoL 5-dimension quality of life scale;
FDA 5 Food and Drug Administration; IR 5 immediate release; LD 5 levodopa; PDQ-39 5 39-item Parkinsons Disease
Questionnaire; PD 5 Parkinson disease; PGI-C 5 Patient Global Impression of Change; PK 5 pharmacokinetics; SAE 5
serious adverse event; SF-36 5 Short Form Health Survey; UPDRS 5 Unified Parkinsons Disease Rating Scale.
Parkinson disease (PD) is the second most common neurodegenerative disorder in the United
States. PD pathology in the form of Lewy bodies is found in the brain and spinal cord, as well
as in the peripheral nervous system, and presents a wide range of clinical manifestations, both motor
and nonmotor. Dopamine modulated circuits are at the core of motor dysfunction in PD. Motor
symptoms of rigidity and bradykinesia respond well to dopaminergic treatment in early PD, with
levodopa (LD) being one of the most effective and widely used treatments for PD.14 The use of LD
therapy for PD is supported by the American Academy of Neurology Practice Guidelines5 because
it improves function and quality of life, reduces morbidity and mortality, and, therefore, reduces
individual and societal costs. Patients with early PD can derive significant benefits from simple
regimens initially, but treatment regimens become more complex with advancing PD, and there is
progressive increase in disability from motor and nonmotor impairment as well as complications of
dopaminergic therapy including development of motor fluctuations in advanced PD.6
LD has a relatively short half-life (;1.5 hours), however, and is quickly and extensively
metabolized in plasma.7,8 A number of formulations have been developed that combine LD with
From the Parkinsons Institute and Clinical Center (R.D.), Sunnyvale, CA; and Parkinsons Disease and Movement Disorder Center of Long Island
(D.L.K.), Commack, NY.
Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
This Neurology supplement was not peer-reviewed. Information contained in this Neurology supplement represents the opinions of the authors. These
opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology.
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Neurology 86 (Suppl 1)
effect and more stable plasma LD levels, resulting in less off time and more on time.
Controlled-release (CR) or sustainedrelease formulations of CD-LD that use a
degradable polymer matrix to slow the release
of LD into the gut have been developed as alternatives to IR formulations. However, a
5-year comparison study noted no difference
in the degree of motor fluctuations and dyskinesias between CR and IR formulations in
patients with moderate to severe motor fluctuations.24 Patients transferred to CR CD-LD
from an IR formulation have not consistently
experienced significant off time reduction.2529 Absorption is delayed (46 hours)30
and symptom relief is less predictable with CR
than with IR.3133 This often requires coadministration of IR with CR, particularly for
the first morning dose, and increases the burden or complexity of the medication schedule
for patients.34,35 CR use is often restricted to
nighttime administration.
CD-LD1 entacapone (CLE) increases total
exposure of IR by 35%40% and prolongs
LD half-life to 2.4 hours. Entacapone inhibits
peripheral LD metabolism and allows more
LD to enter the CNS.36 However, CLE has
been shown to produce LD plasma profiles
similar to CR CD-LD, with higher LD
fluctuations.37
RYTARY (IPX066),
an oral formulation of CD-LD that received US
Food and Drug Administration (FDA) approval in
early 2015, was designed to meet the need for
better LD pharmacokinetics (PK) over existing
preparations. Each RYTARY capsule contains CDLD microbeads designed to dissolve at various rates,
allowing for release and absorption of LD over a
longer timeframe. The CD:LD ratio is 1:4.
Summaries of the key clinical trials for RYTARY
are provided in the sections below.
INTRODUCTION TO RYTARY
April 5, 2016
Figure 1
Mean levodopa (A) and carbidopa (B) plasma concentration time profiles following a single
dose of 2 capsules of extended-release (ER) carbidopa-levodopa (CD-LD) (total dose 97.5
mg CD390 mg LD), immediate-release (IR) CD-LD (25100 mg), controlled-release (CR)
CD-LD (25100 mg), and CD-LD-entacapone (25100200 mg) under fasting conditions.
Source: Hsu A, et al. J Clin Pharmacol 2015;55:9951003.
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Table
RYTARY
IR CD-LD
664
165
p Value
Cmax, ng/mL
3,000 6 1,300
2,360 6 1,100
Tmax, h
2.0 6 1.1
0.87 6 0.5
0.78 6 0.40
0.76 6 0.47
4.0 6 2
1.4 6 0.7
74.5 (60.192.2)
NA
1,248
482
1.23 (0.981.55)
1.07 (0.871.27)
Fluctuation indexa
1.5 6 0.4
3.2 6 1.3
,0.0001
Cmax/Cmin
12.0 6 18.5
82.2 6 67.5
,0.0001
0.0034
,0.0001
0.8998
,0.0001
0.19
Abbreviations: CD-LD 5 carbidopa-levodopa; CI 5 confidence interval; Cmax 5 peak levodopa plasma concentration; Cmin 5 minimum levodopa plasma concentration; IR 5 immediate release; LD 5 levodopa; NA 5 not available; PK 5 pharmacokinetics; Tmax 5 time to Cmax.
Source: Hauser RA, et al. Mov Disord 2011;26:22462252.
a
Fluctuation index 5 (Cmax 2 Cmin)/Cavg (where Cavg is the average concentration over the
12-hour interval on day 8).
a randomized, double-blind, fixed-dose, placebocontrolled study that examined the safety and efficacy
of RYTARY in 381 LD-naive patients with early
PD.41 Patients were not to have been exposed to LD
for .30 days, or have received LD within 4 weeks of
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Neurology 86 (Suppl 1)
April 5, 2016
Figure 2
Mean (SE) Unified Parkinsons Disease Rating Scale (UPDRS) II 1 III over 30 weeks41
TID 5 3 times daily. Source: Pahwa R, et al. Parkinsonism Relat Disord 2014;20:142148.
and 83.4% (n 5 393) completed the 6-week openlabel RYTARY dose conversion. The initial dose of
RYTARY was based on each patients total daily dose
of IR CD-LD at the end of the IR dose adjustment
period. Patients were to start on 3 times/day dosing
with RYTARY, but the dose and dose frequency could
be adjusted by the investigator, with the intention of
reducing off time and minimizing adverse effects.
After the 6-week dose conversion period, patients
were randomly assigned to double-blind treatment
with either RYTARY (186 patients completed) or IR
CD-LD (183 patients completed) for 13 weeks. Four
dose strengths of RYTARY were available for use.42
The 471 patients enrolled in this study had a mean
age of 63.2 years, PD duration of 7.4 years, and mean
daily off time of 5.97 hours.42 The primary efficacy
endpoint, off time as percent of waking hours, was
significantly (p , 0.0001) reduced with RYTARY
(1.17 hours greater reduction) compared with the IR
formulation by study end. Mean daily IR CD-LD dose
was 825.4 mg/d and the mean RYTARY dose was
1,621 mg/d; the mean dosing frequency was 5.2 doses
per day for IR CD-LD and 3.6 doses per day for
RYTARY. Sixty percent of patients required higher
doses of and 16% required lower doses of RYTARY
compared to the dose at the start of conversion; the
dose ratio of RYTARY to IR CD-LD was 2.05. Mean
daily off time is shown in figure 3 for the duration of
the study. Mean on time without troublesome
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Figure 3
Mean daily off time was significantly (p < 0.0001) reduced with RYTARY42
ANCOVA 5 analysis of covariance; CD-LD 5 carbidopa-levodopa; DB 5 double-blind; EOS 5 end of study; IR 5 immediate
release; OL 5 open-label; V 5 visit. Source: Hauser RA, et al. Lancet Neurol 2013;12:346356. *p 5 0.0004 vs IR CD-LD
group, ANCOVA. **p , 0.0001 vs IR CD-LD group, ANCOVA.
Neurology 86 (Suppl 1)
April 5, 2016
Figure 4
Mean percent off time during waking hours, mean off time during
waking hours/day, and mean on time without troublesome dyskinesia
during waking hours/day43
(A) Mean percent off time during waking hours. (B) Mean off time during waking hours/day.
(C) Mean on time without troublesome dyskinesia during waking hours/day. CLE 5 carbidopa-levodopa 1 entacapone. Source: Stocchi F, et al. Parkinsonism Relat Disord
2014;20:13351340.
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S20
Figure 5
led to discontinuation, occurred only in the highdose group.49 Sex (higher rates in females), weight
(higher rates in lighter patients),50 and age (greater
AE rates in patients $75 years of age)51 may also
play a role in rate of AE incidence.
Neurology 86 (Suppl 1)
April 5, 2016
S21
dose of RYTARY than indicated in the dose conversion.42,43 However, adjusting for bioavailability, the
total systemic LD exposure (AUC) was 30%40%
higher with RYTARY than IR CD-LD.40 The
median dosing frequency was 3 times/day after conversion compared with 5 times daily before conversion. In Nausieda et al.,44 the only AE with $5%
incidence was nausea, which was mild or moderate.
There were few discontinuations due to AEs. At the
end of the studies, 86.4% of patients were successfully and safely converted to a stable RYTARY dosage
within a 6-week conversion period.44
Potential role of RYTARY among marketed oral LD
formulations. These clinical results demonstrated that
ACKNOWLEDGMENT
Editorial assistance was provided by Maria B. Vinall of The Curry Rockefeller Group, LLC, Tarrytown, NY, and was funded by Impax Laboratories, Inc. All authors contributed substantially to the analysis and
interpretation of data and/or the drafting and critical revision of the manuscript. All authors gave final approval for submission.
DISCLOSURES
Dr. Dhall has been an investigator in clinical trials sponsored by Impax
Laboratories, Inc. and has been a consultant for Impax, Merz, Teva,
and Acadia Pharmaceuticals. He has participated on speakers bureaus
for Impax, Teva Pharmaceuticals, and UCB. Dr. Kreitzman has been a
principal investigator (PI) for several IPX066 trials and has served on
one Impax Laboratories, Inc., advisory board, for which he received compensation by the sponsor for these activities. He currently is a PI, and has
been so over the past 5 years, for several ongoing clinical trials sponsored
by Adamas Pharmaceuticals, Teva Pharmaceuticals, Pharma Two B Ltd.,
Impax Laboratories, Inc., Neuraltus Pharmaceuticals, Inc., Chelsea Therapeutics, US WorldMeds, LLC, Ipsen Biopharmaceuticals, and ACADIA
Pharmaceuticals Inc. In addition, he currently is a speaker and consultant, and has been so over the past 5 years, for several pharmaceutical
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Neurology 86 (Suppl 1)
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