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Duodenal and gastric delivery of levodopa in parkinsonism.

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Duodenal and Gastric Delivery
of Levodopa in Parlunsonism
Roger Kurlan, MD,* John G. Nutt, MD,? William R. Woodward, PhD,? Kenneth Rothfield, BA,”
David Lichter, MD,” Charlyne Miller, RN, MS,* Julie H. Carter, MN,? and Ira Shoulson, MD”
To clarify the influence of gastric emptying on levodopa-related motor fluctuations in Parkinson’s disease, we assessed
mobility and plasma levodopa concentrations in 10 patients during five modes of levodopa administration: (1)standard
intermittent oral (SIO), (2) intermittent duodenal (ID), (3) continuous duodenal infusion (CDI), (4) continuous gastric
infusion (CGI), and ( 5 ) controlled-release Sinemet (CR-4). The rank order from greatest to least for both percentage of
time “on” and average mobility score was CDI, CGI, ID, CR-4, and SIO. The rank order for variance of means, a
measure of fluctuation, from least to greatest for mobility was CDI, CGI, CR-4, ID, SIO, and for plasma levodopa
concentrations was CDI, CGI, ID, SIO, and CR-4. The results demonstrate that it is possible to produce very steady
plasma concentrations of levodopa with a corresponding reduction in motor fluctuations by continuous intraduodenal
administration of the drug. This mode of delivery is an ideal model for the development of optimal continuous-release
preparations of levodopa. Other enteral routes have produced a more variable plasma levodopa concentration and
clinical response.
Kurlan R, Nutt JG, Woodward WR, Rothfield K, Lichter D, Miller C, Carter JH, Shoulson I. Duodenal and
gastric delivery of levodopa in parkinsonism. Ann Neurol 1988;23:589-595
Fluctuations in the motor performance of levodopatreated patients with Parkinson’s disease are a major
problem in the long-term management of the disorder
[l]. The pathogenesis of this so-called on-off phenomenon remains incompletely understood [2]. However,
patients experiencing motor fluctuations can be maintained reasonably mobile and ambulatory during continuous intravenous infusion of levodopa 13-51, and,
in general, mobility parallels plasma levodopa levels
[S-81. These observations suggest that pharmacokinetic factors, particularly fluctuations in plasma levodopa, are important in the genesis of on-off motor fluctuations.
Levodopa is absorbed from the proximal small intestine and not from the stomach [9]. The stomach, or
more precisely gastric emptying, thus controls delivery
of levodopa to its absorptive site. Clinical and experimental evidence indicates that gastric emptying importantly influences levodopa absorption [9- 161. Erratic
gastric emptying produces variable levodopa absorption and, consequently, fluctuating plasma levodopa
levels. Food, excessive gastric acidity, and other factors
can delay gastric emptying and thereby slow absorption and may be responsible for a lack of responsiveness to individual doses of levodopa 12, 5, 12, 16,
171. Erratic gastric emptying of orally administered
levodopa can be responsible for seemingly random
fluctuations in motor performance for at least some
parkinsonian patients [181. Continuous duodenal infusion of levodopa via nasoduodenal tube improved
mobility and reduced motor fluctuations in 3 parkinsonian patients with the on-off phenomenon 1191. To
clarify further the influence of gastric emptying on
levodopa therapy, we examined 10 additional patients
with parkinsonian fluctuations to compare the efficacy
and pharmacokinetics of different enteral (duodenal
and gastric) modes of levodopa delivery.
From the ‘Department of Neurology, University of Rochester
School of Medicine and Dentistry, Rochester, NY,and the ?Oregon
Health Sciences University, Portland, OR.
Received Sep 8, 1987, and in revised form Dec 1. Accepted for
publication Dec 14, 1987.
Address correspondence to Dr Kurlan, Department of Neurology,
University of Rochester School of Medicine and Dentistry, 601
Elmwood Ave, Rochester, NY 14642.
Materials and Methods
Ten patients (6 from the University of Rochester and 4 from
Oregon Health Sciences University) with idiopathic Parkinson’s disease consented to participate in this investigation.
Duration of illness for the 10 subjects was 15.4 ? 7.1 years
(mean 5 SD) with a range of 8 to 27 years. Duration of
levodopa therapy was 9.7 2 5.0 (range 2-18) years. Eight
patients were classified during their “off” periods in the
Hoehn and Yahr stage IV of illness and 2 were classified as
stage V. All subjects exhibited prominent motor fluctuations
characterized by mobile “on” intervals and immobile (parkinsonian) off periods. The predominant pattern of fluctuations
included: random on-off fluctuations (n = 6), and wearing-
Copyright 0 1988 by the American Neurological Association 589
off (end-of-dose) deterioration with peak-dose dyskinesias
(n = 4). Six patients also experienced frequent sudden transient freezing.
Standard carbidopdlevodopa (Sinemet) therapy had been
adjusted to achieve the optimal level of mobility prior to
hospitalization in our Clinical Research Centers (University
of Rochester and Oregon Health Sciences University). Dosages of other antiparkinsonian medications, including anticholinergics (n = 1) and dopamine receptor agonists (n =
4), remained unchanged throughout the duration of the
study.
Hourly (7 AM to 11 PM) ratings of overall mobility for
parkinsonism (- 5 to 0 scale: 0 = normal mobility, - 5 =
severe parkinsonism) and dyskinesia (0 to + 5 scale: 0 =
none, + 5 = most severe) 118) and hourly plasma sampling
were obtained for all patients during five modes of levodopa
delivery:
1. Phase I -
2.
3.
4.
5.
Standard Intermittent Oral (SIO). Patients received their optimal dosage of Sinemet, taken by standard
oral administration.
Phase If-Intermittent Duoa’enal (ID). A nasoduodenal
(Duo) tube was positioned radiographically with the distal
end in the proximal duodenum, and patients received the
same Sinemet dosage regimen administered in Phase I via
the nasoduodenal tube. Sinemet tablets were dissolved in
15 ml of sterile water and instilled rapidly as a bolus using
a syringe.
Phase Ill-Continuous Duodenal Infusion (CDI). Subjects
received a carbidopdlevodopa solution continuously via
the nasoduodenal tube with the infusion rate regulated by
a mechanical infusion pump. The infusate consisted of 1
gm of levodopa and 250 mg of carbidopa mixed as 1 L of
a 0.001 N hydrochloric acid solution. The infusion period
was from 7 AM to 11 PM daily. The initial infusion rate
was calculated to deliver a total daily levodopa dose that
was 75% of the baseline daily oral Sinemet dose (from
Phase I). The infusion rate was titrated over the next 3 to
5 days to achieve optimal parkinsonian mobility. Proper
localization of the distal end of the tube in the proximal
duodenum was confirmed by fluoroscopy prior to clinical
evaluations and blood sampling on the final day of this
phase.
Phase IV-Continuous Gastric Infusion (CGI). The nasoduodenal tube was pulled back and the distal end was
localized by fluoroscopy to the stomach. The carbidopd
levodopa solution was infused continuously via the tube
at the same infusion rate found to be optimal in Phase 111.
Phase V-Controlled-release Sinemet (CR-4). Following
completion of Phase IV treatment, the tube was removed
and patients then were started on oral controlled-release
Sinemet (CR-4 501200). Initial daily dosage of CR-4 was
calculated to provide 125% of the total daily levodopa
dosage established in Phase I, and the initial dosing interval was approximately twice that established for standard
Sinemet. Subsequently, the dosage and dosing interval of
CR-4 was titrated over 2 to 4 weeks on an outpatient
basis to control the patient’s symptoms. When optimal
parkinsonian mobility was achieved, patients returned to
the Clinical Research Center for clinical assessments and
590 Annals of Neurology
Vol 23 No 6 June 1988
blood sampling by the same protocol as used for the other
phases.
Plasma samples were obtained 0, 15, 30, 45, 60, 90, and
120 minutes after the first morning levodopa dose during
SIO, ID, and CR-4 administration to assess the timing and
magnitude of peak plasma levels of levodopa. In addition, for
1 subject, plasma samples were obtained at 0, 15, 30, and 60
minutes after the 2 PM dose of levodopa during SIO and ID
administration to assess the same parameters for a dose other
than the first of the day. The first morning dose of levodopa
was always given at 7 AM to correspond to the initiation of
clinical ratings and blood sampling. Sampling and clinical assessments during the remainder of the day were at hourly
intervals. Plasma samples were assayed for levodopa concentration by high pressure liquid chromatography (HPLC)
[20]. In addition, plasma samples obtained at 8 AM, 2 PM,
and 8 PM during each of the five phases were analyzed by
HPLC for the concentration of 3-0-methyldopa (3-0-MD),
a major metabolite of levodopa.
Analysis of variance (ANOVA) was used to compare the
various measurements, and the significance of differences
between pairs of means was evaluated by a t test using the
pooled variances.
Results
Ten subjects completed phases I through IV and 8
completed Phase V. Mobility ratings and plasma levodopa levels during each of the five phases for a representative subject are illustrated in Figures 1 to 5. Total
daily levodopa dosages were similar for all phases
(Table). Mean plasma levodopa levels were lower for
intermittent than continuous modes of levodopa administration (see Table). Plasma levodopa levels during
the initial 4 hours of continuous duodenal (Phase 111)
and gastric (Phase IV) infusion rose slowly into the
therapeutic ranges, usually correlating with a gradual
appearance of clinical response (Figs 3,4). This initial 4
hours was eliminated for comparative assessments of
mobility and plasma levodopa so that analyses between
the different routes of administration were based on
the 12-hour time period 11 AM to 11 PM,when plasma
levodopa levels were stable.
Each mode of levodopa administration was compared to the standard oral route (Phase I) with respect
to evaluations of efficacy and pharmacokinetic parameters. Phase I1 (ID) delivery produced no difference in
mobility ratings or motor fluctuations. Patients with
random fluctuations in mobility tended to have more
predictable fluctuations in relationship to the timing of
levodopa dosing than with the oral route. Plasma levodopa levels also varied more predictably in relation to
levodopa dosing than with oral administration. Plasma
levodopa concentrations were decreased for this route
even though the same total daily levodopa dosage was
administered. This may represent more rapid absorption of the drug so that peak plasma concentrations
-'i
-lV
-I
-4
Fig I . Mobility ratings and plasma levodopa (L-DOPA)concentrations during standurd intermittent oral therapy (Phase I) for
a representativesubject. Levodopa dosing tims are indicated b~
asterisks.
were not measured by hourly sampling. Indeed, the
more frequent sampling after the first dose of the day
showed that peak plasma concentrations occurred generally within 30 minutes of oral administration and
within 15 minutes of duodenal administration (see Figs
1 and 2). This shortening of the time to peak plasma
levodopa level and the slight increase in the magnitude
of the peak relative to that afeer oral administration did
not attain statistical significance. Frequent plasma sampling after the 2 PM dose in 1 subject showed no
evident rise in plasma levodopa following oral administration (Fig 6, top), indicating failure or delay of drug
absorption, but a rapid rise h e r duodenal delivery (Fig
6, bottom). There was no difference in fluctuation
(mean variance) of plasma levodopa levels (see Table).
Mean plasma 3-0-MD concentrations were no different than with the standard oral route (see Table).
-41
Fig 2. Mobility ratings and plasma levodopa (L-DOPA)concentrations during intermittent duodenal delivery (Phase 11)for the
same representative subject. Levodopa dosing times are indicated
by asterisks.
Phase I11 (CDI) resulted in better mean mobility ( p
< 0.01) and an increase in the percentage of on ratings
( p C 0.05) when compared to the standard oral route.
Motor fluctuations, as measured by variance of mobility, were reduced ( p < 0.03). Plasma levodopa levels
were higher ( p < 0.001) even though levodopa dosage
was not significantly greater than with oral delivery.
Fluctuations of plasma levodopa were reduced ( p <
0.01) compared to standard oral therapy. Plasma 3-0MD levels were similar to those with oral administration. CDI produced the best mean mobility, highest
mean plasma levodopa level, and lowest variance for
mobility and plasma levodopa of all routes (ANOVA).
Although total daily levodopa dosage was changed
during the CDI titration phase in 9 subjects (increased
in 5, decreased in 4 ) to achieve optimal mobility during the infusions, the mean total daily levodopa dosage
Kurlan
et al: Duodenal and Gastric Levodopa
591
'1
t
1
).
.,
0
0
:i
-s
-=r
-*
-4
-4
- 2 0
,
\
I
0
15
E
7W
.OD
900 IWO 1100 1200 1300 IIW 1-0
1.W 1700 1.W 1.W oo00
El00 ilLw
TIM!
Fig 3. Mobility ratings and plasma levodopa (L-DOPA)concentrations during continuous duodenal infusion (Phase III) (7 AM
to 11 PM, for the same representative subject.
Fig 4 . Mobility ratings and plasm levodopa (L-DOPA)concentrations during continuous gastric infusion (Phase IV) (7 A M to
11 PM) for the same representative subject.
for Phases I11 and IV showed no difference from those
used in Phases I and 11.
Phase IV (CGI) administered the same total daily
levodopa dosage as used in Phase 111. Continuous gastric infusion produced a significant ( p < 0.01) improvement in mobility ratings compared to the standard oral route, but significantly less improvement
than with CDI ( p < 0.001). Fluctuations were not
lessened. Plasma levodopa levels were also higher
for CGI compared to the oral route, although fluctuations were not significantly reduced. No difference in
plasma 3-0-MD concentrations was observed. Following initiation of the infusions, plasma levodopa levels
generally rose more slowly during gastric delivery than
during duodenal delivery.
Phase V (CR-4) did not significantly improve mobility or motor fluctuations. Mean plasma levodopa levels
were higher than during regular Sinemet administration (Phase I). This difference may have reflected the
slightly higher total daily levodopa dosage used, although dosage differences were not statistically different. No change in plasma levodopa fluctuations was
observed. Time to peak plasma level was greatly delayed for this route ( p < 0.01) compared to that for
patients receiving the standard oral Sinemet formulation, although the magnitude of the peak level was the
same. Plasma 3-0-MD levels were significantly ( p <
0.001) elevated during CR-4 administration compared
to those during oral therapy with the standard Sinemet
formulation (Phase I).
592
Annals of Neurology Vol 23
No 6 June 1988
Discussion
We have assessed the clinical efficacy and pharmacokinetic behavior of five different enteral modes of
levodopa delivery, each at dosages judged to produce
optimal mobility. The study was designed to evaluate
the influence of location of enteral delivery (gastric
or duodenal) and the mode of administration (inter-
TI#€
h
700
UH)
wo
LOOO ~ S O D1200 1300 1400
a w iwo
1700 1.00
isoo a m zaoo moo
T I Y
Fig 5 . Mobility ratings and plasma levohpa (L-DOPA)concentrations during controlled-release Sinemet (CR-4) therapy (Phase
V )for the same representative subject. CR-4 dosing times are
indicated by asterisks.
mittent or continuous) on levodopa absorption and
clinical efficacy. Although total daily levodopa dosages
were lowest during intermittent delivery of levodopa
(Phases I and 11), hgher during levodopa infusions
(Phases I11 and IV), and highest during controlledrelease Sinemet administration (Phase V), these dosage
differences were not statistically significantly different,
and therefore levodopa dosage was likely not an important factor in our analyses.
Although intermittent direct duodenal delivery of
levodopa produced no significant differences in mobility ratings or motor fluctuations when compared to
standard oral administration, duodenal delivery was associated with more predictable clinical responses and
elevations of plasma levodopa in relationship to individual levodopa doses. This effect is likely mediated by
more rapid absorption due to bypassing the stomach
and variable gastric emptying. Although time to peak
plasma level was briefer and the magnitude of the peak
slightly higher for duodenal than oral delivery, the difference did not attain statistical significance for our
sample size. Analysis of the rapidity of absorption with
more frequent plasma sampling was performed after
the first levodopa dose of the day; this dose is generally
the best absorbed of the day. We suspect that rapid
and complete absorption for duodenal delivery would
be present throughout the day but that absorption of
oral doses would be more unpredictable later in the
day as reported by Melamed 1171 and supported by
our assessment of plasma Ievodopa after a midafternoon dose in 1 of our subjects (see Fig 6, top).
The clinical difference between oral and intermittent
duodenal administration was most dramatically illustrated by a patient who experienced random fluctuations in mobility during oral levodopa therapy, but a
pronounced pattern of recurrent end-of-dose deterioration when the same levodopa regimen was delivered
via nasoduodenal tube. This patient is being reported
separately elsewhere { 181.
Both continuous duodenal and gastric infusion
routes produced improved mobility compared to standard oral therapy. Overall mobility was better and fluctuations in mobility and plasma levodopa were less
with duodenal administration than with gastric, although for some patients the two routes were equivalent. These observations indicate that delivery of the
drug distal to the pylorus is ideal to avoid capricious
gastric emptying. The mode of delivery has an important influence as well. Continuous administration of
levodopa via duodenal infusion is superior to intermittent dosing. The production of more steady levels of
plasma levodopa is likely responsible for this benefit.
Furthermore, even with continuous infusion, the rapidity of absorption was generally greater for the
duodenal than the gastric route, thus confirming that
gastric emptying may delay drug absorption.
Controlled-release Sinemet (CR-4), a preparation
designed to provide slow and steady release of levodopa in the stomach, showed no overall beneficial effect for mobility or motor fluctuations when compared
to the standard oral form for this group of patients
with advanced disease. Some individual subjects did
show a good response, however (see Fig 5). Our
observation of improved mobility during continuous
gastric infusion of levodopa suggests that sustainedrelease preparations of Sinemet may ultimately prove
superior to the standard formulation. Time to peak
plasma level was significantly delayed for CR-4 in comparison to the standard formulation and was accompanied by slower onset of therapeutic benefit (see Figs
1, 5). This observed delay in achieving peak plasma
level following CR-4 administration confirms an earlier
report [21). The elevation of plasma 3-0-MD levels
during CR-4 therapy could be a factor contributing to
Kurlan
et al: Duodenal and
Gastric Levodopa 593
Levodopa Dosage, Mobility Assessments, Plasma Lpyodopa Measurements, and Plasma 3-0-Methyldopa Concentrations
During 5 Modes of Enteral Levodopa Delivery"
Plasma Levodopa
Magnitude
ofpeak
Level
(nmoUrn1)
Plasma
Variance
Time to
Peak
Level
(fin)
5.2
15.9 f 12.3
34.3 f 11.3
16.8 2 6.7
44.6
2 3 . 6 2 8.0
17.4f4.2
41.6211.6
Mobility
3-0-MD
Mode of
Administration
No.
Subjects
Total Daily
Levodopa
Ratings
Dosage (mp) On (%)
I
Standardintermktent
10
1,155 2 402
55
I1
Intermittent
duodenal
Continuous
duodenal
infusion
Continuous
gastric
infusion
Controlledrelease
Sinemet
10
1,155?402
70229
O.l?1.9
2.1k1.8
7.3i3.9'
8 . 9 ~7.2
10
1,304 ? 594
83
1.1 ? 1.5'
0.9 t l.3b 12.6 2 6.1d
1.9 ~ f : 1.6'
41.8
?
18.9
10
1,304 2 594
73 -c 31
0.3
1.6 2 1.8
11.8 i 5Bd
6.5
40.8
5
15.0
8
1,327 ? 362
60
1.9
11.6
59.8
?
17.3d
Phase
2
29
Rating
-0.3
?
Concentration
(nmollml)
Variance
1.9
2.6
i
1.9
9.8
?
Concentration
(nmoVm1)
?
14.4
Oral
111
IV
V
~
~~
~
~~
~
?
2
31b
35
2
1.7'
-0.1 t 1.9
2
1.8
i
5.2'
5
9.0
21.6 2 14.4
80.0 2 34.6'
15.9 2 8.9
~~~
Values given are the means t SD. Variance for mobility and plasma levodopa represents the mean of the variances for each patient. Statistical significance indicates differences
from Phase I.
'p < .05.
'p <: .01.
dp i .001.
-
PO
a
\
Y
I
15
t
:
10
I
s
0
800
WO
1000
1100
1200
1300
1.00
1100
1.00
1700
la00
LYOO
la00
1WO
2000
2100
2'200
2100
2200
TIYL
800
SO0
1000
1100
ll00
1300
1400
1500
1.00
1100
2000
T I M
Fig 6. Plasma levodopa (L-DOPA)concentrations j i r a different
subject during standurd zntemittent oral therapy (PhaseI )
(top)and internittent duodenal udminzstration (Phase 11) (bottom).Lmodopa dosing times are indicated by asterisks. No rise
in plasm levodopa zs evident after the 2 PM oral levodopa dose
(top arrowhead),but a rapid rise in plasma levodopa is seen
afer the 2 Phiduodenal levodopa dose (bottom arrowhead).
594 Annals of Neurology Vol 23 No 6 June 1988
its delayed clinical effect, although our evidence from
other studies suggests that this s m d increment in
plasma 3-0-MD would likely be clinically insignificant
1221.
Our findings confirm the beneficial effects of continuous enteral infusions of levodopa, particularly via
the duodenal route, and suggest that this benefit is
linked to consistent drug absorption and, consequently, to more steady plasma levels. These results
emphasize the contribution of erratic gastric emptying
to unpredictable absorption of orally administered
levodopa and resultant fluctuations in plasma levodopa
and mobility. Optimal therapy for parkinsonian motor
fluctuations must circumvent this pharmacokinetic obstacle. Continuous duodenal administration of levodopa is impractical for long-term therapy, but the
benefits of this mode of delivery can set the goal for
which to aim in the development of sustained-release
preparations of levodopa and other strategies such as
enteral pouches 1231.
Supported by Merck, Sharp & Dohme Research Laboratories, NIHR01 NS 21062, and Public Health Service research grants RR00044 (Rochester) and RR-00334 (Oregon) from the General Clinical Research Centers Branch, Division of Research Resources,
National Institutes of Health.
We thank Mrs Ruth Nobel for preparation of the manuscript.
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Kurlan et al: Duodenal and Gastric Levodopa 595
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