Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa–Levodopa

16 Pages·2017·0.59 MB·English

by  Aravind Mittur

ClinPharmacokinet(2017)56:999–1014
DOI10.1007/s40262-017-0511-y
REVIEW ARTICLE
Pharmacokinetics of Rytary(cid:2), An Extended-Release Capsule
Formulation of Carbidopa–Levodopa
Aravind Mittur1 • Suneel Gupta1 • Nishit B. Modi1
Publishedonline:24February2017
(cid:2)TheAuthor(s)2017.ThisarticleispublishedwithopenaccessatSpringerlink.com
Abstract Parkinson’s disease (PD) is a chronic progres- pharmacodynamics of this ER product of carbidopa–levo-
sive neurological disorder characterized by resting tremor, dopa in healthy subjects and in patients with PD.
rigidity, bradykinesia, gait disturbance, and postural
instability. Levodopa, the precursor to dopamine, coad-
ministered with carbidopa or benserazide, aromatic amino
Key Points
acid decarboxylase inhibitors, is the most effective and
widelyusedtherapeuticagentinthetreatmentofPD.With
Rytary(cid:3) (Numient(cid:3), IPX066) is an extended-release
continued levodopa treatment, a majority of patients
(ER) capsule formulation of carbidopa–levodopa
developmotorcomplicationssuchasdyskinesiaandmotor
that combines immediate-release (IR) and ER beads
‘on-off’ fluctuations, which are, in part, related to the
to provide a rapid onset of effect that is then
fluctuations in plasma concentrations of levodopa. A new
sustained for a longer duration than standard
extended-release(ER)carbidopa–levodopacapsuleproduct
formulations of carbidopa–levodopa.
(also referred to as IPX066) was developed and approved
in the US as Rytary(cid:3) and in the EU as Numient(cid:3). The For comparable doses of levodopa, Rytary(cid:3) results
capsule formulation is designed to provide an initial rapid in 30% maximum observed plasma concentration
absorption of levodopa comparable to immediate-release and 70% area under the concentration–time curve
(IR) carbidopa–levodopa, and to subsequently provide compared with IR levodopa.
stable levodopa concentrations with reduced peak-to- Rytary(cid:3) and IR carbidopa–levodopa have a similar
trough excursions in plasma concentrations in order to
concentration–effect relationship based on the
reduce motor fluctuations associated with pulsatile stimu-
Unified Parkinson’s Disease Rating Scale Part III,
lation of dopamine receptors and to minimize dyskinesia.
and finger tapping rate.
Phase III studies of this ER carbidopa–levodopa capsule
formulation in patients with PD have shown a significant
reduction in ‘off’ time compared with IR carbidopa–levo-
dopa and carbidopa–levodopa–entacapone. We present a
1 Introduction
review of the clinical pharmacokinetics and
Parkinson’s disease (PD) is characterized by the progres-
Electronicsupplementarymaterial Theonlineversionofthis sive degeneration of nigrostriatal dopaminergic neurons.
article(doi:10.1007/s40262-017-0511-y)containssupplementary
Levodopa (L-3,4-dihydroxyphenylalanine), the metabolic
material,whichisavailabletoauthorizedusers.
precursor of dopamine, in combination with aromatic
& NishitB.Modi amino acid decarboxylase (AADC) inhibitors such as car-
[email protected] bidopa or benserazide, is considered the most effective
treatment for management of the loss of mobility associ-
1 ImpaxSpecialtyPharma,aDivisionofImpaxLaboratories
ated with PD.
Inc.,31047GenstarRoad,Hayward,CA94544,USA
1000 A.Mitturetal.
The oral absorption, central nervous system (CNS) there is a clear relationship between gastric emptying and
penetration, and distribution of levodopa are mediated by levodopa absorption [11].
active transporters. Levodopa is actively absorbed and Although dopamine agonists have longer plasma half-
transported across the intestinal mucosa and blood–brain lives than levodopa, cause less pulsatile stimulation of
barrier(BBB).L-andB(0,?)-typeaminoacidtransporters dopamine receptors,and are used for therapy in the earlier
(LAT1, LAT2, rBAT, and their oligomers with the stages of PD, they are not as efficacious as levodopa and
heterologous proteins 4F2hc, TAT1, and OCT) have been suffer from common side effects. The use of COMT inhi-
implicated in the oral and CNS absorption of levodopa bitors, such as entacapone, with carbidopa–levodopa
[1–4].Theabsorptionoflevodopaisrestrictedtotheupper reduces‘off’timebutlargefluctuationsinlevodopaplasma
small intestine. Once absorbed, levodopa is converted to concentrations still occur in their presence [12, 13]. Enta-
dopaminebyAADCandismetabolizedto3-O-methyldopa caponealsoadverselyaffectstherateatwhich dyskinesias
(3-OMD) by catechol-O-methyltransferase (COMT), develop on carbidopa–levodopa treatment when started
among other metabolites. Inhibitors of AADC and COMT early in disease [14]. Levodopa remains indispensable in
are coadministered with levodopa to suppress the periph- the treatment of PD, especially in the later stages of the
eral formation of dopamine, reduce the exogenous dose of disease, and there is a clinical need for an improved oral
levodopa by maximizing the amount of levodopa trans- carbidopa–levodopa product that can consistently deliver
ported across the BBB, and reduce adverse effects of stable levodopa plasma concentrations.
peripheral dopamine, such as nausea and hypotension. Thedevelopmentprogramforthisnewextended-release
Continuous stimulation of striatal dopaminergic recep- (ER) capsule formulation of carbidopa–levodopa (also
tors remains the goal and is a current unmet need of oral referred to as IPX066) included studies to characterize the
pharmacotherapy for PD. With progression of PD and pharmacokinetics in healthy volunteers and patients with
chronic therapy, levodopa is often associated with the PD, and to evaluate dose proportionality, and the effect of
development of involuntary motor function complications food and intrinsic factors on the pharmacokinetics. Both
such as ‘on-off’ phenomena, ‘wearing-off’, and dyskinetic the safety and efficacy of this ER carbidopa–levodopa
movements.Themostcommonformofdyskinesia,termed product have been reported previously [15–17]. This
‘peak-dose dyskinesia’, coincides with peak plasma levels review focuses on the integrated pharmacokinetic and
oflevodopa.Althoughanumberoffactorscontributetothe pharmacodynamic properties of this ER capsule formula-
development of motor complications in levodopa therapy, tion of carbidopa–levodopa.
pulsatile levodopa administration and high levodopa doses
are considered key factors [5–7].
Multiple therapeutic strategies, including oral con- 2 Drug Formulation
trolled-release (CR) formulations and intestinal/jejunal
infusion, have been attempted to provide continuous and IPX066,anERcapsuleformulationofcarbidopa–levodopa
sustainedoraldeliveryoflevodopainanefforttoreduceor (Rytary(cid:3) in the US and Numient(cid:3) in the EU), is designed
delay the development of dyskinesias. Current oral CR toprovideaplasmaprofilecharacterizedbyaninitialrapid
productssuchSinemet(cid:3)CR,whichisabsorbedover4–6 h, increase in levodopa concentrations followed by sustained
are associated with erratic absorption and variable levo- levodopa concentrations with minimal peak-to-trough
dopa plasma concentrations. The absorption of Sinemet(cid:3) fluctuations. This profile provides a rapid onset of effect
CR is less predictable than that of Sinemet(cid:3) immediate- andreduces‘off’timeinPDsubjects.Theformulationisa
release (IR) and may require supplemental doses of IR combinationoflevodopaandcarbidopaataratioof4:1and
carbidopa–levodopa [8]. The effect of Sinemet(cid:3) CR on is available in four strengths: 23.75/95, 36.25/145, 48.75/
dyskinesias is also often difficult to predict. Continuous 195, and 61.25/245 mg carbidopa–levodopa. The formu-
controlled oral delivery of levodopa has been a challenge lation contains four components: an IR component, ER
due to its short plasma half-life, unreliable absorption due component 1, ER component 2, and a functional excipient
to delayed and/or variable gastric emptying, variable component. The IR component, ER component 1, and ER
in vivo dissolution of levodopa products, and absorption component 2 contain both levodopa and carbidopa as
being limited to the small intestine where the transporters active ingredients, while the fourth component does not
for levodopa are located. Gastrointestinal dysfunction is a contain levodopa or carbidopa but includes tartaric acid as
key non-motor symptom in PD across all stages of PD, a functional excipient serving as an acidifying agent
with studies reporting impaired gastric emptying and con- designed to facilitate the absorption of levodopa. The
stipation.Gastroparesisisobservedin70–100%ofsubjects four components of the ER carbidopa–levodopa formula-
[9, 10] and can lead to response fluctuations, including tionexhibitdifferentindividualdrug-releasecharacteristics
delayed‘on’orlackofan‘on’(no‘on’phenomenon),and and are designed todeliver the initial increase in levodopa
PharmacokineticsofRytary(cid:3) 1001
• studythesingle-dosepharmacokineticsrelativetoother
marketed carbidopa–levodopa formulations in healthy
volunteers;
• evaluatetheeffectoffoodandofemptyingthecapsule
contents onto soft foods such as applesauce;
• studythedoseproportionalityofthepharmacokinetics;
• characterize the effects of intrinsic factors such as age,
gender, and weight on the pharmacokinetics
3.1 Single-DosePharmacokineticsinHealthyAdults
The single-dose pharmacokinetics of ER carbidopa–levo-
dopacapsuleswas compared withthe pharmacokinetics of
other currently available formulations of carbidopa–levo-
Fig.1 Pharmacokinetic profile for immediate-release CD-LD, indi- dopa in healthy subjects in an open-label, randomized,
vidual extended-release components and intact capsules of Rytary(cid:3).
crossover study [18]. Subjects received a single oral dose
Data presented are LD concentrations from different studies that
of ER carbidopa–levodopa (two capsules of 48.75/195 mg
evaluated the performance of individual components and the phar-
macokineticsofextended-releaseCD-LDcapsules.CDcarbidopa,LD carbidopa–levodopa), IR carbidopa–levodopa (25/100 mg
levodopa Sinemet(cid:3)), CR carbidopa–levodopa (25/100 mg Sinemet(cid:3)
CR) or carbidopa–levodopa–entacapone (25/100/200 mg
Stalevo(cid:3)) under fasting conditions. The levodopa dose of
concentrations and provide the sustained plasma profile.
ER carbidopa–levodopa (390 mg) was chosen to approxi-
Early in development, pharmacokinetic studies were con-
mately match the expected peak levodopa concentrations
ducted in healthy volunteers to evaluate various combina-
for IR carbidopa–levodopa [18]. With ER carbidopa–
tions of IR and formulations designed to release levodopa
levodopa capsules, levodopa plasma concentrations
over a range of durations to allow selection of the desired
increasedrapidly,reachinganinitialpeakatapproximately
in vivo levodopa profile. Figure 1 presents the plasma
1 h, with mean time to maximum concentration (t )
max
concentration profile for IR levodopa, ER component 1
occurring at approximately 4.5 h, after which levodopa
beads, and ER component 2 beads at levodopa doses from
concentrationsdecreasedslowlyandwere\10%ofpeakat
theindividualcomponentsthatwouldcorrespondtoatotal
approximately 10 h. The pharmacokinetics of levodopa
dose of 390 mg. Also presented is the pharmacokinetic
fromthedifferentformulationsaresummarizedinTable 1.
profileforasingledoseof390mgERcarbidopa–levodopa
In spite of a 3.9-fold higher levodopa dose with ER car-
intact capsule (two capsules of levodopa 195 mg). The
bidopa–levodopacomparedwiththeothertreatments,peak
combinationoftheIRandtwoERformulationcomponents
levodopa concentrations were approximately 1.2- to 1.6-
allows achievement of the desired levodopa pharmacoki-
fold higher. As expected, area under the concentration–
netic profile characterized by a rapid initial increase fol-
timecurve(AUC)valueswereapproximately2.2-to3-fold
lowing by sustained levodopa plasma concentrations.
higher. The bioavailability of levodopa from ER car-
bidopa–levodopa capsules relative to IR carbidopa–levo-
dopa, CR carbidopa–levodopa, and carbidopa–levodopa–
3 Pharmacokinetics
entacapone was 83.5, 78.3, and 58.8%, respectively. In
comparison, on a dose-normalized basis, peak plasma
The clinical development program to characterize the
concentrations of levodopa from ER carbidopa–levodopa
pharmacokinetics and pharmacodynamics of ER car-
relative to IR carbidopa–levodopa, CR carbidopa–levo-
bidopa–levodopa included the following goals:
dopa, and carbidopa–levodopa–entacapone were 31.3,
• characterize the single and multiple dose pharmacoki- 40.0,and33.4%,respectively.Theabsolutebioavailability
neticsandpharmacodynamicsrelativetoIRcarbidopa– oflevodopafromIRcarbidopa–levodopahasbeenreported
levodopa in patients with PD; to be 84% [19]. Hence, the absolute bioavailability of
• characterize the single dose pharmacokinetics and levodopa from ER carbidopa–levodopa capsules is
pharmacodynamics relative to CR carbidopa–levodopa approximately70%(the83.5%bioavailabilityoflevodopa
and relative to carbidopa–levodopa–entacapone in from ER carbidopa–levodopa relative to IR carbidopa–
patients with PD; levodopa multiplied by 0.84).
1002 A.Mitturetal.
Table1 Single-dosepharmacokineticparametersforlevodopainhealthysubjects(n=22)AdaptedfromHsuetal.[18]
Producta C (ng/mL) t (h)b AUC (ngh/mL) t (h) C ratio F(%)
max max ? (cid:2) max
ERCD-LD390mg 1326±268 4.5(0.5–8.0) 7244±2553 1.9±0.7 – –
IRCD-LD100mg 1094±401 1.0(0.5–2.0) 2251±664 1.6±0.2 0.34±0.10 83.5±21
CRCD-LD100mg 855±299 1.5(1.0–2.0) 2403±680 1.6±0.2 0.43±0.16 78.3±20
CD-LD-Entacapone100mg 1027±284 1.5(1.0–2.0) 3291±1149 1.6±0.2 0.35±0.11 58.8±18
ERextended-release,IRimmediate-release,CRsustainedrelease,LDlevodopa,CDcarbidopa;C maximumobservedplasmaconcentration,
max
t timetomaximumconcentration,t half-life,C ratiodose-normalizedratioofERCD-LDC toreferenceproduct,AUC areaunder
max (cid:2) max max ?
theconcentration–timecurveextrapolatedtoinfinity,Frelativebioavailability
a Thedoseslistedareforlevodopa
b Median(range)
3.2 Single-Dose Pharmacokinetics in Patients
with Parkinson’s Disease (PD)
The single-dose pharmacokinetics of ER carbidopa–levo-
dopacapsulesinpatientswithPDwasinvestigatedrelative
to IR carbidopa–levodopa (Sinemet(cid:3)), CR carbidopa–
levodopa (Sinemet(cid:3) CR), and carbidopa–levodopa–enta-
capone (Stalevo(cid:3)), each in a separate crossover study
[17, 20]. In these studies, patients took a single dose of
their typical pre-study IR carbidopa–levodopa regimen
following an overnight fast on one occasion, and ER car-
bidopa–levodopa on a separate occasion. The dose of ER
carbidopa–levodopawasbasedonaconversiondesignedto
achieve similar peak levodopa concentrations as the com-
parator treatments. Based on pharmacokinetic data in
healthy volunteers that ER carbidopa–levodopa results in
dose-adjusted levodopa maximum observed plasma con-
centrations (C ) that are approximately 31.3% on IR
max
carbidopa–levodopa,itwas expectedthat the ER levodopa Fig.2 Single-dose pharmacokinetics of IR and ER CD-LD in
patients with Parkinson’s disease. ER extended-release, IR immedi-
doses would be at least twofold higher. Figure 2 presents
ate-release,CDcarbidopa,LDlevodopa
the levodopa plasma concentration–time profile following
single doses ofIR carbidopa–levodopa andER carbidopa–
levodopa capsules. As noted in healthy subjects, levodopa levodopa relative to IR carbidopa–levodopa and car-
concentrations peaked within approximately 1 h and then bidopa–levodopa–entacapone was 69 ± 23 and 47 ± 16,
decreased rapidly following IR carbidopa–levodopa. With respectively. Due to the short sampling duration in the
ER carbidopa–levodopa capsules, the initial increase in pharmacokinetic study, the bioavailability of levodopa
levodopa concentrations was similar to that noted with IR from ER carbidopa–levodopa relative to CR carbidopa–
levodopa, but levodopa concentrations were sustained for levodopa was not estimated.
4–5 h following the peak. In addition, in spite of an
approximate two- to five-fold higher levodopa dose with 3.3 Multiple-Dose Pharmacokinetics in Patients
ER carbidopa–levodopa, peak levodopa concentrations with PD
were comparable to IR dosing. The single-dose pharma-
cokinetics of ER carbidopa–levodopa and the other car- Multiple-dose pharmacokinetics of ER carbidopa–levo-
bidopa–levodopa products in patients are presented in dopa compared with IR carbidopa–levodopa was charac-
Table 2. On a dose-normalized basis, the levodopa C terizedinpatientswithadvancedPD[20].Patientsreceived
max
from ER carbidopa–levodopa compared with IR car- an individualized dosing regimen of ER carbidopa–levo-
bidopa–levodopa,CRcarbidopa–levodopa,andcarbidopa– dopa and IR carbidopa–levodopa for 8 days in a crossover
levodopa–entacapone were 30.5, 52.2, and 29.7%, respec- fashion, with multiple-dose pharmacokinetic assessment
tively.ThebioavailabilityoflevodopafromERcarbidopa– carried out over 12 h on the last day of each treatment
PharmacokineticsofRytary(cid:3) 1003
Table2 Single-dose Product C (ng/mL) t (h)a AUC (ngh/mL) t (h)
max max ? (cid:2)
pharmacokineticsofERCD-LD
inpatientswithPDcompared ERCD-LDcapsules
withotherCD-LDproducts
LD435mg(n=12) 1686±970 1.5(1–6) – –
LD490mg(n=16) 2424±763 2.5(0.5–4) 11291±3945 1.6±0.5
LD585mg(n=7) 2936±1360 1.5(0.5–2.5) 15210±8905 2.4±0.9
LD735mg(n=14) 3058±701 1.5(0.5–3) 13221±3756 1.5±0.2
LD780mg(n=3) 3703±1220 2(0.5–2.5) 18424±4093 2.2±1
LD980mg(n=6) 4967±1040 2(0.5–4.5) 20479±3257 1.7±0.1
IRCD-LD
LD100mg(n=11) 1870±697 0.5(0.5–1.5) 3173±1090 1.5±0.4
LD200mg(n=10) 2331±769 1.3(0.5–2) 5978±1830 1.5±0.2
LD250mg(n=4) 3935±1570 0.5(0.5–1) 7690±1090 1.6±0.1
CRCD-LD
LD200mg(n=12) 1453±814 2(1–4) 5000±3070b –
CD-LD-Entacapone
LD100mg(n=10) 2105±897 1(0.5–1.5) 7223±3640 1.8±0.3
LD150mg(n=6) 2493±837 1(0.5–2) 8655±5320 1.8±0.2
LD200mg(n=4) 3038±756 1.3(1–2) 10936±3924 1.7±0.4
ThepharmacokineticsforERCD-LDcapsulesarebasedondataintegratedfromthreestudies
C maximumobservedplasmaconcentration,t timetomaximumconcentration,t half-life,AUC
max max (cid:2) ?
areaundertheconcentration–timecurveextrapolatedtoinfinity,CDcarbidopa,LDlevodopa,ERextended-
release,IRimmediate-release,CRcontrolled-release,PDParkinson’sdisease
a Median(range)
b AUC reported
t
period.Duringthefirst3 daysofeachtreatmentperiod,the
dosing regimen (dose and frequency) was adjusted as
necessarytoachieveoptimalefficacywithreducedadverse
effects. For the ER carbidopa–levodopa capsule treatment,
89%ofpatientstookoneortwodoses,and11%tookthree
doses over the 12-h assessment period, with no subject
taking more than four doses. In contrast, during the IR
carbidopa–levodopatreatment,37%ofpatientstookoneor
two doses, 26% took three doses, and 37% took four or
more doses over the 12-h assessment period. Figure 3
presents the multiple-dose levodopa concentration–time
profile for ER carbidopa–levodopa and IR carbidopa–
levodopa over the 12-h assessment period. Multiple dose
pharmacokinetics of ER and IR carbidopa–levodopa are
summarized in Table 3. The magnitude of rise and fall of
Fig.3 Multiple-dose pharmacokinetics of IR and ER CD-LD in
levodopa plasma concentrations relative to the average
patients with Parkinson’s disease. Arrows represent oral dose
concentration (i.e. the fluctuation index) may be of par-
administrations every 3 or 6h. ER extended-release, IR immediate-
ticular interest for an ER formulation. The lower the fluc- release,CDcarbidopa,LDlevodopa,Qxheveryxhours
tuationindex,themorelikelytheC isbluntedrelativeto
max
the trough, thus improving the pharmacodynamic profile approximatelyevery6 hinaccordancewiththeprescribing
and minimizing C -related adverse effects [21]. The guidelines.
max
fluctuation index measured as (C - C )/C was 1.5
max min ave
and 3.2 for ER carbidopa–levodopa and IR carbidopa– 3.4 Dose Proportionality
levodopa, respectively. Both treatments had a similar
accumulationratioindicatingthattheERformulationdoes The dose proportionality of ER carbidopa–levodopa cap-
not result in accumulation of levodopa when administered sules was evaluated in a single-dose, open-label,
1004 A.Mitturetal.
Table3 Multiple-dose Product C (ng/mL) C (ng/mL) Accumulation Fluctuation
max ave
pharmacokineticsofERCD-LD
andIRCD-LDinpatientswith ERCD-LDcapsules
PD
LD490mg(n=7) 3227±1089 1623±518 1.3±0.4 1.7±0.4
LD735mg(n=11) 4166±1787 2316±777 1.3±0.8 1.4±0.4
IRCD-LD
LD100mg(n=11) 2209±744 741±203 1.1±0.3 3.0±1.1
LD200mg(n=9) 3057±1108 969±384 1.1±0.3 3.3±1.0
C maximumobservedplasmaconcentration,C averageconcentrationover12h,Accumulationdrug
max ave
accumulation, Fluctuation fluctuation calculated as (C -C )/C , ER extended-release, IR imme-
max min ave
diate-release,CDcarbidopa,LDlevodopa,PDParkinson’sdisease
randomized, crossover study in healthy subjects [22]. ER
carbidopa–levodopa was provided as one capsule of each
dose strength (levodopa 95, 145, 195, 245 mg), and each
subject received a single dose of each treatment with
240 mLofroom-temperaturewaterunderfastedconditions
in a randomized sequence. Dose proportionality was
assessed using a power model (Y = a 9 [Dose]b), as
described by Gough et al. [23], with the modification by
Smithetal.[24]Doseproportionalitywastobeconcluded
if the proportionality exponent estimate (b) for levodopa
C and AUC was close to unity and the 90% confidence
max
intervals (CIs) were within the acceptance interval
(0.7645–1.2355).
Atotalof31healthysubjectswereenrolled;28subjects
received all four treatments and were included in the sta-
tistical analysis. Online Resource Table 1 presents the
pharmacokinetic and dose-proportionality analysis. ER
carbidopa–levodopa showed dose-proportional pharma-
cokineticsoverthecapsulestrengthrangeof95/245 mgof
levodopa. The power-model analysis confirmed that the
90% CI for the proportionality exponent estimate (b) for
C , AUC, and AUC were within the acceptance
max t ?
interval, indicating dose proportional pharmacokinetics.
Dose proportionality of the ER carbidopa–levodopa
capsules was also examined using the pooled single-dose
pharmacokinetic data in patients with advanced PD from
thepharmacokineticcohortenrolledintheefficacystudies.
Levodopa C and AUC increased in an approximate
max ?
dose-proportional fashion over the broad range of doses
administered (Fig. 4).
3.5 Comparison of Pharmacokinetics in Healthy
Subjects and Patients with PD
Fig.4 Relationship between LD dose and LD pharmacokinetics in
The pharmacokinetics of ER carbidopa–levodopa capsules patients with Parkinson’s disease. C maximum observed plasma
max
has been studied in multiple studies in healthy volunteers concentration, AUC area under the concentration–time curve
?
[18,22]andinpatientswithadvancedPD[17,20].Table 4 extrapolatedtoinfinity,LDlevodopa
summarizes the levodopa pharmacokinetics in healthy in the levodopa pharmacokinetics of ER carbidopa–levo-
subjects and in patients following normalization to a dopabetweenhealthysubjectsandpatientswithPD.Mean
levodopa dose of 245 mg. Modest differences were noted dose-normalized levodopa AUC and C were higher
? max
PharmacokineticsofRytary(cid:3) 1005
Table4 Summaryofdose-normalizedlevodopapharmacokineticsinhealthysubjectsandpatientswithPDfollowingERCD-LD
C (ng/mL) t (h)a AUC (ngh/mL) t (h)
max max ? (cid:2)
Healthysubjects(N=184) 822±259 4.0(0.3–8.0) 3884±1285 1.7±0.7
PDpatients(N=72) 1130±484 2.0(0.5–6.0) 5579±2465 1.9±0.7b
C andAUC aredose-normalizedto245mg
max ?
C maximumobservedplasmaconcentration,t timetomaximumconcentration,AUC areaundertheconcentration–timecurveextrap-
max max ?
olatedtoinfinity,t half-life,ERextended-release,CDcarbidopa,LDlevodopa,PDParkinson’sdisease
(cid:2)
a Median(range)
b N=59
(approximately 44 and 38% for AUC and C , respec- PD.Consistentwiththesustainedlevodopaconcentrations,
? max
tively)insubjectswithPDcomparedwithhealthysubjects. the duration of pharmacodynamic effect following ER
The elimination half-life for levodopa was comparable in carbidopa–levodopa capsules is approximately 2 h longer
the two populations. than that for IR carbidopa–levodopa or carbidopa–levo-
dopa–entacapone forbothtapping andUnifiedParkinson’s
3.6 Maintenance of Levodopa Plasma Disease Rating Scale (UPDRS) Part III (motor function)
Concentrations scores [17, 20].
The ER carbidopa–levodopa capsule formulation is 3.7 Low Variability in Pharmacokinetics
designed to provide an initial increase in levodopa con-
centrations that are comparable to IR carbidopa–levodopa Variability (percentage of coefficient of variation) in
and subsequently maintain the levodopa concentration for levodopa pharmacokinetics may be estimated as a ratio of
an extended period of time. Table 5 summarizes the thestandarddeviation(SD)andmean.Table 6summarizes
duration of time levodopa plasma concentrations are sus- the variability in levodopa pharmacokinetics for ER car-
tained above 50% of C in both healthy subjects and bidopa–levodopa capsules compared with other levodopa
max
patients with PD for ER carbidopa–levodopa and other products from the study in healthy volunteers [18]. Inter-
marketed carbidopa–levodopa products following a single subject variability in C was lower, and for AUC was
max t
dose. lower or comparable for ER carbidopa–levodopa capsules
ER carbidopa–levodopa sustains levodopa plasma con- than for other carbidopa–levodopa products.
centrations above 50% of C for a longer duration Several studies conducted in healthy volunteers as part
max
(4–5 h)thanIRcarbidopa–levodopa(approximately1.5 h), of the development of ER carbidopa–levodopa capsules
CRcarbidopa–levodopa(2–3 h),andcarbidopa–levodopa– involved a crossover design that allowed estimation of
entacapone (2–2.5 h) in healthy subjects and subjects with intersubject (between subject) and intrasubject (within
PD.Notably,theestimateddurationthatconcentrationsare subject) variability. Natural logarithmically-transformed
sustained above 50% C was consistent across the dose-normalized C and AUC were analyzed by anal-
max max ?
studies and in both healthy volunteers and patients with ysis of variance using a linear mixed model to obtain
Table5 Comparisonofdurationoftime(hours)theLDconcentrationsaresustainedabove50%ofC byCD-LDproductsfollowingasingle
max
dose.DatapresentedareMean±SD
Product Healthysubjects PDpatients
Hsuetal.[18](N=22) Study1(N=27) Study2(N=32) Study3(N=12)
ERCD-LD 4.9±2.4 4.0±2.0 4.1±1.5 4.1±1.3
IRCD-LD 1.5±0.7 1.4±0.7 NA NA
CRCD-LD 2.1±1.0 NA NA 3.1±1.0
CD-LD-Entacapone 2.1±1.0 NA 2.5±1.1 NA
NA not applicable, ER extended-release, IR immediate-release, CR sustained release, LD levodopa, CD carbidopa, C maximum observed
max
plasmaconcentration,SDstandarddeviation
1006 A.Mitturetal.
Table6 Intersubject variability (% CV) in LD pharmacokinetics crossover study, subjects received two capsules of ER
fromERCD-LDcapsulesandotherCD-LDproducts carbidopa–levodopa 61.25/245 mg under fasting condi-
tions, and then, after an appropriate washout of at least
ERCD-LD IRCD-LD CRCD-LD CD-LD-
Entacapone 6 days, received two capsules of ER carbidopa–levodopa
61.25/245 mg after consuming a high-fat, high-calorie
C 20.2 36.7 35.0 27.7
max breakfast as recommended by US Food and Drug Admin-
AUC 30.9 30.0 28.8 34.9
t istration (FDA) and European Medicines Agency (EMA)
Cmaxmaximumobservedplasmaconcentration,AUCtareaunderthe guidance [29, 30]. On a separate occasion, subjects
concentration–time curve from time zero to the last measured con-
received the contents of carbidopa–levodopa capsules
centration,ERextended-release,IRimmediate-release,CRsustained
sprinkled over a tablespoon of applesauce under fasting
release,LDlevodopa,CDcarbidopa,CVcoefficientofvariation
conditions.AdministrationofERcarbidopa–levodopawith
a high-fat, high-calorie breakfast delayed the initial
estimates of intra- and intersubject variabilities for these increase in levodopa concentration by approximately 2 h,
parameters using pooled data from the crossover studies. reduced C by 21%, and increased AUC by 13%
max ?
Intrasubject variability was 17.2% for log AUC? and compared with the fasted state. Sprinkling the ER car-
18.8% for log Cmax, whereas intersubject variability was bidopa–levodopa capsule contents on applesauce did not
22.2% for log AUC? and 19.8% for log Cmax. These affect the pharmacokinetics [22].
intrasubject variabilities would be considered low accord-
ing to the commonly used regulatory definition that drugs
thatexhibitintrasubjectvariabilityof[30%areconsidered 4 Effect of Intrinsic Factors
highly variable [26–28]. on the Pharmacokinetics of ER Carbidopa–
The multiple-dose pharmacokinetics of ER carbidopa- Levodopa Capsules
levodopa and IR carbidopa–levodopa was compared in
patients [20]. Over the 12-h assessment period, the average The effect of various intrinsic factors, including race,
interindividualcoefficientofvariationforplasmaconcentra- gender, age, body weight, and renal function, on the
tionsoflevodopaafterERcarbidopa–levodopatreatmentwas pharmacokinetics of ER carbidopa–levodopa was evalu-
33.2%,significantlylowerthanduringIRcarbidopa–levodopa ated using dose-normalized data from studies in healthy
administered every 6 h (75.2%) or IR carbidopa–levodopa volunteers and patients.
administeredevery3 h(43.0%)(p\0.05,Bartlett’stest).
4.1 Effect of Race
3.8 Effect of Food on the Pharmacokinetics
ofExtended-Release(ER)Carbidopa–Levodopa The vast majority (95%) of patients with PD in whom
Capsules pharmacokinetic data were available were White; there-
fore,noassessmentsofraceonlevodopapharmacokinetics
Thesustained-releasebeadsintheERcarbidopa–levodopa were conducted in patients with PD. In the healthy popu-
capsule formulation are designed to exhibit lower drug lation, levodopa C and AUC values were 10–17%
max ?
release below pH 7. The effect of two representative soft- higherinBlackversusWhitesubjects.Mediantimetopeak
food products [Jell-O (pH 6.5) and Kozy-Shack Flan levodopa concentration and terminal half-life were com-
Cre`meCaramelPudding(pH6.1)]withpHvaluesabove6 parable in the two groups (Table 7).
was investigated to evaluate the in vitro release of levo-
dopa. Approximately 10 mL of each food was mixed with 4.2 Effect of Gender
ER component 2 beads and allowed to stand at ambient
temperaturefor30 min.Thebeadswerewashedwithwater Plasma concentrations of levodopa were higher in women
until no food residue was visible and the amounts (%) of compared with men, in both healthy subjects and patients
levodopa and carbidopa remaining in the beads were with PD. In healthy subjects, mean dose-normalized levo-
determined. Mixing ER carbidopa–levodopa with selected dopa C values were approximately 25% greater and
max
softfoodswithapHofapproximately6.0forupto30 min AUC values approximately 38% higher in females than
?
resulted in\4.5% levodopa release and did not affect the inmales,whileinpatientswithPD,meandose-normalized
integrity of the formulation, as demonstrated by the C was 35% greater and AUC was 37% higher in
max ?
insignificant amount of levodopa released upon mixing. females than in males. Median time to peak levodopa
Theeffectofahigh-fatmealonthepharmacokineticsof concentration and terminal plasma half-life of levodopa
single-dose ER carbidopa–levodopa was also investigated were comparable in men and women for both healthy
in healthy volunteers [22]. In a three-period, randomized, subjects and patients with PD (Table 8).
PharmacokineticsofRytary(cid:3) 1007
Table7 LDpharmacokinetics White(N=121) Black(N=61) Ratio(Black/White)
forERCD-LDcapsulesin
healthysubjectscategorizedby C (ng/mL) 793±269 873±224 1.10
max
race(mean±SD)
t (h)a 4.0(0.3–7.0) 4.5(0.5–8.0) –
max
t (h) 1.7±0.9 1.7±0.5 1.0
(cid:2)
AUC (ngh/mL) 3679±1252 4294±1284 1.17
?
AUC andC aredose-normalizedto245mg
? max
C maximumobservedplasmaconcentration,t timetomaximumconcentration,t half-life,AUC
max max (cid:2) ?
area under the concentration–time curve extrapolated to infinity, SD standard deviation, ER extended-
release,CDcarbidopa,LDlevodopa
a Median(range)
4.3 Effect of Age subjects and patients with PD. Body weight accounted for
approximately 18 and 31% of the observed variability in
Patients with PD in whom pharmacokinetic data were dose-normalized C and AUC of levodopa, respec-
max ?
available were significantly older than healthy subjects; tively, in patients with PD (Online Resource Fig. 2). As
93% of patients with PD were older than 50 years of age, expected, no difference in t and t was observed
max (cid:2)
while 98%ofhealthysubjectswere younger than 50 years between the weight groups.
of age.
Dose-normalized levodopa AUC increased with 4.5 Effect of Renal Function
?
increasing age in healthy subjects and patients with PD.
Age accounted for approximately 4% and 15% of the The relationship between estimated creatinine clearance, a
variability in levodopa AUC in healthy volunteers and measure of renal function, and levodopa pharmacokinetics
?
patients with PD, respectively (Online Resource Fig. 1), was evaluated using the pooled dose-normalized pharma-
and mean dose-normalized C and AUC were 27 and cokinetic data from studies in healthy volunteers and
max ?
52% higher, respectively, in patients with PD older than patientswithPD.Dose-normalizedAUC valuestendedto
?
65 years of age compared with patients younger than increase with decreasing creatinine clearance in both
50 years of age. healthy subjects and patients with PD (Online Resource
Fig. 3). Estimated creatinine clearance explained approxi-
4.4 Effect of Body Weight mately 14 and 18% of the variability in AUC in healthy
?
subjects and patients with PD, respectively, and accounted
Table 9summarizeslevodopapharmacokineticsinhealthy for approximately 13 and 14% of the variability in levo-
subjectsandpatientswithPD,byweight.Dose-normalized dopa C in healthy subjects and patients with PD,
max
C andAUC oflevodopafromERcarbidopa–levodopa respectively.
max ?
were negatively correlated with body weight in healthy
Table8 LDpharmacokinetics C (ng/mL)a t (h)b t (h) AUC (ngh/mL)a
max max (cid:2) ?
forERCD-LDcapsulesin
healthysubjectsandpatients Healthysubjects
withPDcategorizedbygender
Males(N=97) 734±211 4.0(0.3–6.0) 1.7±0.30 3291±874
(mean±SD)
Females(N=87) 920±273 3.5(0.3–8.0) 1.7±0.78 4545±1351
SubjectswithPD
Males(N=52) 1029±405 1.5(0.5–6.0) 1.9±0.7c 5103±2218c
Females(N=20) 1390±580 2.0(0.5–3.0) 1.9±0.9d 6975±2695d
PD Parkinson’s disease, C maximum observed plasma concentration, t time to maximum concen-
max max
tration,t half-life,AUC areaundertheconcentration–timecurveextrapolatedtoinfinity,ERextended-
(cid:2) ?
release,CDcarbidopa,LDlevodopa,SDstandarddeviation
a Dosenormalizedto245mg
b Median(range)
c N=45
d N=15
1008 A.Mitturetal.
Table9 Pharmacokineticsof C (ng/mL)a t (h)b t (h) AUC (ngh/mL)a
max max (cid:2) ?
ERLDcapsuleinhealthy
subjectsandsubjectswithPD Healthysubjects
categorizedbybodyweight
40to\65kg(N=42) 991±279 4.5(0.5–8.0) 1.7±0.77 4911±1504
65–91kg(N=119) 799±224 3.5(0.3–7.0) 1.7±0.72 3744±1012
C91kg(N=23) 631±218 3.5(0.3–6.0) 1.7±0.30 2730±722
SubjectswithPD
40to\65kg(N=8) 1509±649c 1.5(0.5–3.0)c 2.1±1.1 8781±2330
65–91kg(N=34) 1148±439c 2.0(0.5–6.0)c 1.8±0.5 5457±2352
C91kg(N=18) 917±347c 2.0(0.5–3.5)c 1.9±0.8 4380±1307
C maximumobservedplasmaconcentration,t timetomaximumconcentration,t half-life,AUC
max max (cid:2) ?
area under the concentration–time curve extrapolated to infinity, PD Parkinson’s disease, ER extended-
release,LDlevodopa
a Dosenormalizedto245mg
b Median(range)
5 Pharmacodynamics transporters are expressed and the extent of absorption
depends on the rate at which levodopa transits through the
The pharmacokinetic/pharmacodynamic relationship for upper small intestine. The absolute oral bioavailability of
ERcarbidopa–levodopacapsuleshasbeencharacterizedin levodopa is dose-dependent due to capacity-limited
patients with PD using finger tapping, UPDRS Part III absorption via the active transporters. In practice, doses of
score, and the incidence of dyskinesia [25]. The pharma- levodopa are carefully titrated in each patient to achieve
codynamic models included a biophase effect site equili- optimal efficacy. Low concentrations of levodopa in
brationwithasigmoidmaximumeffect(E )transduction plasma (and in the brain) can result in the reappearance of
max
for tapping and UPDRS Part III score, and an ordered the core symptoms of PD; however, side effects such as
categorical model for dyskinesia. Pharmacodynamic motorfluctuations,occurwhenlevelsoflevodopaexceeda
parameters for tapping and UPDRS Part III scores are patient-specific threshold. Furthermore, uncontrolled and
presented in Online Resource Table 2. The estimated half unpredictable fluctuations in plasma and striatal concen-
maximal effective concentration (EC ) for tapping was trations of levodopa are thought to contribute to the
50
1590 ng/mL,withanequilibriumhalf-lifeof36 min,while development of ‘on-off’ fluctuations, including dyskine-
the EC for the UPDRS Part III score was 812 ng/mL, sias. Therefore, the treatment of motor symptoms in PD is
50
with an equilibrium half-life of 23 min, and the EC for mosteffectivewhenplasmaconcentrationsoflevodopaare
50
dyskinesiawas601 ng/mL,withanequilibriumhalf-lifeof maintainedwithinatherapeuticrange,whichprogressively
27 min [25]. narrows as the disease progresses.
In addition, a dose-response relationship for UPDRS Although several controlled-release (CR) formulations
Part II plus Part III was established in levodopa-na¨ıve PD of levodopa (with carbidopa or benserazide) have been
patientsusingadiseaseprogressionmodel[31].Themodel developed, these formulations are associated with erratic
comprised three components: a linear function describing absorption and variable levodopa plasma concentrations
natural disease progression, a component describing pla- [32, 33]. In addition, the latency to onset of motor
cebo (or non-levodopa) effects, and a component describ- improvement is typically 60–180 min with the CR for-
ing the levodopa-specific effect. Natural disease mulation due to the slower absorption. Thus, CR formu-
progression in early PD was 11.6 units/year and the half lations are commonly administered with IR carbidopa–
maximal effective dose (ED ) for the total daily dose of levodopa in patients, particularly for the first dose in the
50
levodopa was 450 mg [31]. morning [34, 35]. Various methods, including oral CR
formulations and duodenal infusion of levodopa, have
soughttoprovidecontinuousandsustainedoraldeliveryof
6 Discussion levodopainanefforttoreduceordelaythedevelopmentof
motor complications. With the exception of invasive and
Oral levodopa is rapidly absorbed across the intestinal often impractical continuous intraduodenal infusion of
mucosa by amino acid transporters expressed in the prox- levodopabyapump,currentregimensoforallevodopaare
imalsmallintestine.Therefore,oralabsorptionoflevodopa beset by a limited window of effect, requiring frequent
is largely limited to the intestinal region where these administrations and/or unpredictable pharmacokinetics.