REVIEW

Current Practices for Outpatient Initiationof Levodopa-Carbidopa Intestinal Gelfor Management of Advanced Parkinson’s Diseasein the United States

Fahd Amjad . Danish Bhatti . Thomas L. Davis . Odinachi Oguh .

Rajesh Pahwa . Pavnit Kukreja . Jorge Zamudio . Leonard Verhagen Metman

Received: March 27, 2019 / Published online: July 5, 2019� The Author(s) 2019

Abstract: In 2015, the US Food and DrugAdministration approved levodopa-carbidopaintestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for thetreatment of motor fluctuations in patients withadvanced Parkinson’s disease. LCIG provides acontinuous infusion of levodopa and carbidopaby means of a portable pump and percutaneousendoscopic gastrojejunostomy tube. The deliv-ery system has a two-fold pharmacokineticadvantage over orally administered carbidopa/

levodopa. First, levodopa is delivered in a con-tinuous rather than intermittent, pulsatilefashion. Second, delivery to levodopa’s site ofabsorption in the jejunum bypasses the stom-ach, thereby avoiding issues with erratic gastricemptying. In blinded prospective clinical trialsand observational studies, LCIG has beenshown to significantly decrease ‘‘off’’ time,increase ‘‘on’’ time without troublesome dyski-nesia, and reduce dyskinesia. Consistent withprocedures in previous studies, LCIG initiationand titration in the pivotal US clinical trial wereperformed in the inpatient setting and followeda standardized protocol. In clinical practice,however, initiation and titration of LCIG have a

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F. Amjad (&)Department of Neurology, Georgetown UniversityHospital Pasquerilla Healthcare Center, 7th Floor,3800 Reservoir Road NW, Washington, DC 20007,USAe-mail: Fahdvr@hotmail.com

D. BhattiDepartment of Neurological Sciences, University ofNebraska Medical Center, 988440 Nebraska MedicalCenter, Omaha, NE 68198, USA

T. L. DavisDepartment of Neurology, Vanderbilt UniversityMedical Center, 1301 Medical Center Drive #3930,Nashville, TN 37212, USA

O. OguhDepartment of Neurology, University of FloridaCollege of Medicine—Jacksonville, 9th Floor, TowerI, 580 West 8th Street, Jacksonville, FL 32209, USA

R. PahwaDepartment of Neurology, University of KansasMedical Center, 3599 Rainbow Blvd, Kansas City, KS66103, USA

P. Kukreja � J. ZamudioAbbVie, Inc, 1 North Waukegan Road, NorthChicago, IL 60064, USA

L. V. MetmanDepartment of Neurological Sciences, RushUniversity, 1725 W Harrison Street, Suite 755,Chicago, IL 60612, USA

Adv Ther (2019) 36:2233–2246

https://doi.org/10.1007/s12325-019-01014-4

great degree of flexibility and, in the US, almostalways take place in the outpatient setting.Nonetheless, there remains a significantamount of clinician uncertainty regardingtitration in outpatient clinical practice. Thisreview aims to shed light on and provide guid-ance as to the current methods of titration inthe outpatient setting, as informed by themedical literature and the authors’ experiences.Funding: AbbVie, Inc.Plain Language Summary: Plain languagesummary available for this article.

PLAIN LANGUAGE SUMMARY

Results from recent studies have shown thatcontinuous infusion of levodopa-carbidopaintestinal gel (LCIG) into the jejunum (a part ofthe small intestine) effectively manages themotor and nonmotor complications (e.g., tre-mor, extreme stiffness in arms and legs, diffi-culty walking, and impaired balance)experienced by patients with advanced Parkin-son’s disease (PD). LCIG is administered by aportable pump directly into the patient’s jeju-num by a permanent tube that is inserted sur-gically. LCIG therapy is beneficial to advancedPD patients over orally administered carbidopa/levodopa for two reasons. First, oral carbidopa/levodopa moves from the stomach to the smallintestine where it is intermittently absorbedinto the blood stream. LCIG is administeredcontinuously and offers better symptom controlfor longer. Results from clinical trials andobservational studies have shown that LCIGsignificantly decreases ‘‘off’’ time (poor motorcontrol) and increases ‘‘on’’ time (good motorcontrol) in advanced PD patients without trou-blesome dyskinesia, which results from thehigher doses of oral levodopa required to treatthe symptoms. Second, LCIG is absorbed in thejejunum, thereby bypassing the stomach whereproblems can occur because of inconsistentstomach emptying. In the US, titration of LCIGis performed mostly in an outpatient setting.Some clinicians may view titration of LCIG tobe too complex and variable, so they avoidusing LCIG therapy for their PD patients.

Fortunately, emerging data and clinicians’expanding experience with LCIG have shownthat titration can be easily managed in an out-patient setting, allowing for more customizedtherapeutic regimens for patients.

Keywords: Carbidopa/levodopa enteral suspen-sion; Continuous dopaminergic stimulation;Device-aided therapy; Duodopa; Duopa; LCIG;Neurology

INTRODUCTION

Levodopa-carbidopa intestinal gel (LCIG;known in the US as carbidopa-levodopa enteralsuspension) is an aqueous carboxymethylcellu-lose gel suspension containing four parts levo-dopa to one part carbidopa monohydrate(4.63 mg carbidopa and 20 mg levodopa perml), the same ratio as that provided in oralcarbidopa-levodopa 25–100 tablets. LCIG isadministered via a portable pump directly tothe proximal small intestine through a percu-taneous endoscopic gastrojejunostomy (PEG-J)tube (Fig. 1) [1]. This system delivers medicationto the site of levodopa absorption, thus avoid-ing issues associated with delayed or variablegastric emptying. Delivery of levodopa viainfusion also permits finer adjustments in dosethan are possible with oral administration. Themode of administration combined with con-tinuous medication flow allows LCIG to providemore consistent circulating levels of levodopaand carbidopa compared with immediate-re-lease oral carbidopa/levodopa treatment [2].The goal of this approach is, hopefully, to gen-erate sustained rather than intermittent stimu-lation of striatal dopaminergic neurons, therebypreventing the occurrence of ‘‘off’’ periods inpatients with advanced Parkinson’s disease (PD)[3].

LCIG (Duopa, AbbVie, Inc., North Chicago,IL, USA) was approved in the US in January2015 for the treatment of motor fluctuations inpatients with advanced PD, although it hasbeen available in other parts of the world for[10 years (known as Duodopa� outside the US).LCIG has been shown to significantly reduce

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‘‘off’’ time and increase ‘‘on’’ time withouttroublesome dyskinesia in patients withadvanced PD [4–11]. Marked improvementshave also been observed in non-motor symp-toms (e.g., sleep/fatigue, attention/memory,mood/cognition, gastrointestinal tract, urinary,sexual function) and in quality-of-life measures[6–8, 10–12]. Benefits related to LCIG haveproved to be durable [8–11], with reductions inmean daily ‘‘off’’ time maintained for as long as9 years after initiating LCIG therapy [13].

The process of initiating and titrating LCIGhas evolved with clinical studies and experi-ence. When first introduced in Europe, a trialperiod of LCIG administration via a nasojejunaltube was standard to assess the patient’sresponse prior to moving forward with PEG-Jtube placement. By the advent of the first UStrial, however, this was not considered a nec-essary introductory step; patients who metstudy-entry criteria proceeded to PEG-J tubeplacement without the intermediary test period

[6]. During the pivotal US trial, patientsremained in the hospital for up to 2 weeks afterPEG-J tube placement, at which time LCIGtreatment was initiated and titration com-menced [6]. This step has also been streamlinedover time. In US clinical practice, LCIG initia-tion and titration are typically performed in theoutpatient setting, an approach that is sup-ported by findings in a recently published open-label, phase 3b study [10]. Clinical experiencehas yielded additional insights into the LCIGinitiation and titration process, includingidentification of points in the process that canbe optimized to meet patient and practiceneeds. In this review, we use clinical data andexperience to guide clinicians through the stepsinvolved in converting patients to LCIG therapyin the outpatient setting. This article is based onpreviously conducted studies and the authors’clinical experience and does not involve anynew studies of human or animal subjects per-formed by any of the authors.

Fig. 1 The levodopa-carbidopa intestinal gel (LCIG) system. PEG percutaneous endoscopic gastrojejunostomy. Imagereproduced from Clin Transl Gastroenterol (Creative Commons license CC BY-NC-ND 4.0) [1]

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CANDIDATE DETERMINATION

As noted above, LCIG therapy requires place-ment of a PEG-J tube. However, prior to PEG-Jtube placement, patients are evaluated by theirneurologist to determine if they are appropriatecandidates for LCIG, as indicated by the pres-ence of ‘‘off’’ periods despite optimized treat-ment with oral PD medications. The neurologistmay also verify that the patient’s most relevantsymptoms are still levodopa responsive. Duringthe pre-LCIG assessment, the patient manage-ment team will determine whether the patientcan manage therapy on his or her own or, if acaregiver is needed, the support available issufficient. In addition, the patient will need tobe evaluated by the proceduralist (e.g., gas-troenterologist, interventional radiologist orgeneral surgeon) who will place the PEG-J tubeto ensure the procedure will be feasible and thepatient has no clinical or anatomic limitationsthat would interfere with tube placement.

A 2015 consensus statement [14] from aninternational panel of experts suggested thatintrajejunal levodopa infusion is considered asboth therapeutic and palliative in some coun-tries for patients who have cognitive impair-ment or dementia. This group also suggestedthat LCIG may be considered for patients aged[70 years who have mild or moderate cogni-tive impairment or severe depression. More-over, emerging clinical data support the safe useof LCIG in patients with PD and cognitiveimpairment [15]. In our clinical experience, theLCIG initiation and titration process does notdiffer among those individuals with cognitiveimpairment compared with individuals whohave normal cognitive function.

INITIAL TITRATION

A schematic of the titration process from thePEG-J procedure through follow-up is presentedin Fig. 2. The interval between placement of thePEG-J tube and initiation of LCIG is variable. Inthe outpatient titration study by Standaert andcolleagues [10], the protocol mandated thatLCIG was to be initiated within 5 days of thePEG-J procedure. Approximately two-thirds of

patients commenced LCIG within 24 h of PEG-Jtube placement, and 90% had started LCIGwithin 48 h of the PEG-J procedure. On theother end of the spectrum, the outpatientmodel presented by Fasano et al. [16] recom-mends a minimum of 2 weeks between PEG-Jtube placement and LCIG initiation ‘‘to allowthe fistula track to establish’’, thereby poten-tially reducing the risk for site-related compli-cations. Adverse events that occur morefrequently during the early phases of LCIGtreatment compared with the maintenancephase are often related to the procedure (e.g.,procedural pain, stoma site irritation) [10].Standard practice in the US involves schedulingpatients for their first titration visit approxi-mately 1 week after the PEG-J procedure toallow for adequate healing time, air absorptionfrom the abdomen, and discontinuation of painmedications, which can affect treatmentresponse. In rare cases such as when the patientlives a long distance from the clinic and hastravel/logistic concerns, rapid initiation (i.e.,within 24 h of PEG-J tube placement) may beconsidered.

The objective of the first visit is not toachieve the optimal dose, rather it is to achievetherapeutic benefit with further fine-tuningperformed by the patient and clinician, either athome or in the office. Based on our clinicalexperience, during the first titration visit,patients will spend 1–6 h in the clinic, depend-ing on the patient and clinician. A recent studyreported similar findings [median time spenttitrating LCIG was 3 h (range 0.5–5 h)] [17]. Onarrival at the clinic, a brief motor examinationis completed to provide a point of comparisonfor assessing response to therapy. Monitoringand pump programming are performed byclinic staff (e.g., nurse, nurse practitioner,physician assistant, or medical assistant), withperiodic assessments made by the movementdisorder specialist/neurologist.

DETERMINING INITIAL LCIGDOSAGE

The initial total daily dose of LCIG is calculatedby adding the patient’s total daytime oral

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levodopa dose and the levodopa equivalentdose of other PD medications (if these medica-tions are to be discontinued at the time oftransition to LCIG). The majority of cliniciansdo not discontinue other PD medications untilthe patient is stabilized on his or her levodopadose to help mitigate unwanted side effects

such as dopamine agonist withdrawal syndrome[18], restless legs, increased akinesia and soforth. In most cases, the patient will receiveLCIG treatment for 16 h per day and, if needed,oral levodopa for nighttime coverage. Treat-ment with oral levodopa during the day isreplaced by the LCIG infusion.

Fig. 2 Schematic of the levodopa-carbidopa intestinal gel(LCIG) titration process. Shaded rectangles indicateclinical touch points. Diamonds indicate decision points,including rapid (within 24 h) versus delayed initiation of

LCIG after percutaneous endoscopic gastrojejunostomy(PEG-J) tube placement, arriving at the first visit in the‘‘on’’ versus ‘‘off’’ states and Lock Level 1 versus Lock Level2 programming. PD Parkinson’s disease

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Although the goal of LCIG is not to providemonotherapy, adjunctive treatment may not beneeded. Moreover, most patients appreciate nolonger having to take multiple medicationsseveral times a day. The monotherapy andpolytherapy approaches were compared indi-rectly by Lew and colleagues [19] in theirassessment of two phase 3 clinical trials. In thefirst clinical trial, a 54-week, open-label study[8], 92% of patients were receiving LCIGmonotherapy at 4 weeks after the PEG-J proce-dure [19]. Although 80% of patients had beenon polytherapy at screening and adjunctivetherapy was permitted after the initial 4-weektreatment period, 76.5% of patients remainedon monotherapy throughout the 54-weekstudy. In contrast, in the second clinical trial, a12-week, double-blind, placebo-controlledstudy [6], only oral levodopa was stopped (andreplaced by LCIG) while other PD medicationswere continued at stable doses in 84% ofpatients [19]. Efficacy and safety results werecomparable whether a monotherapy or poly-therapy approach was taken. Moreover, in asubsequent analysis of data from the 54-weekstudy, the LCIG safety profile was similar whenused as monotherapy or polytherapy [20].Notably, the rates and types of adverse eventswere similar in patients who received LCIG ororal carbidopa/levodopa in the 12-week study[6]. There may be an advantage to amonotherapy approach in that it minimizes thepotential for side effects from long-term use ofother PD medications. Dopamine agonists, forexample, were recently linked to impulse con-trol disorders among patients with PD, the riskfor which increased with lifetime average dailydose and duration of treatment [21]. Theseeffects resolved over time after patients discon-tinued treatment with dopamine agonists.Interestingly, treatment with LCIG has beenshown to progressively reduce the symptoms ofimpulse control disorder, possibly because LCIGprovides more stable plasma levodopa levelsthan does oral levodopa [22, 23].

A table for determining the levodopa equiv-alent dose of anti-parkinson medications hasbeen previously published by Tomlinson et al.[24]. We have reproduced this table here, withupdated information such as dose equivalence

for carbidopa/levodopa extended-release cap-sules (Rytary; Impax Pharmaceuticals, Hayward,CA, USA) [25] and dose-conversion adjustmentsbased on clinical experience (Table 1).

LCIG is provided as single-use, 100-ml cas-settes containing 4.63 mg carbidopa and 20 mglevodopa per ml [26]. LCIG is administeredaccording to three dosing programs: (1) amorning bolus dose, (2) a continuous mainte-nance dose and (3) extra doses that can beadministered as needed. The morning-dosevolume is typically calculated by multiplyingthe patient’s standard morning levodopa dose(in mg) by 0.8 and dividing the product by20 mg/ml (the concentration of LCIG in thecassette). The 0.8 multiplier is used to reducethe risk for dyskinesia; the dose can then betitrated up or down, depending on the suffi-ciency of the dose. An extra 3 ml is then addedto prime the PEG-J tube. An example of themorning-dose calculation is presented in Fig. 3.After the morning-dose administration, whichtypically takes 10–30 min depending on thevolume being administered, the device auto-matically transitions to the continuous-doseprogram.

The continuous infusion rate is determinedby subtracting the morning levodopa dose (ascalculated above) from the total daytime levo-dopa daily dose, divided by the number ofhours that the infusion was active. The resultingamount in milligrams is then divided by 20 mg/ml to yield the total LCIG volume that will beadministered during the day (except for themorning bolus dose). The hourly infusion rate iscalculated by dividing the total LCIG dailyvolume by the duration of infusion (usually16 h). An example of the continuous-dose ratecalculation is shown in Fig. 3.

These morning- and continuous-dose ratecalculations provide a starting point fromwhich to make refinements. Suggestions fortailoring LCIG dosing are provided in Table 2.For example, a patient who before transition toLCIG had been receiving a large morning doseof oral levodopa ([ 150 mg) designed to last3–4 h may benefit from a smaller LCIG morningbolus dose (e.g., 60% of the pre-LCIG doserather than the 80% used in the standard cal-culation) because of the continual levodopa

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infusion with LCIG. Changes in dose will alsobe guided by patient response and tolerability.The goal of the initial titration visit is to achievea dose that is neither too high (thus, resulting inexcessive dyskinesia, hallucinations/abnormalthinking or behavior) or too low (resulting in‘‘off’’ time or insufficient improvement insymptoms or objective measures). In cases ofsignificant dyskinesia or dose-responsive sideeffects, the LCIG dose may need to be reduced.Conversely, if the patient experiences ‘‘off’’periods, the continuous dose may need to beincreased. Similarly, if the morning dose doesnot reliably induce an ‘‘on’’ state, the doseshould be increased. Prescribing guidelinessuggest that the morning dose should beincreased by 1–2 ml on the subsequent day if

the patient demonstrates an inadequate clinicalresponse within 1 h of morning-dose adminis-tration [26]. Often clinicians give patients andcaregivers the ability to change the pump set-ting to increase or decrease the continuous doseby up to 0.5 ml per h, as needed. When clini-cians give (appropriate) patients the opportu-nity to adjust the infusion rate (within apredetermined range), they make the patientessentially a partner in the titration process. Inthis scenario, the initial titration visit in theclinic can be significantly shortened.

Extra LCIG doses may be self-administeredby the patient, as clinically indicated. The LCIGpump allows healthcare providers to setparameters (i.e., volume and time intervalbetween administrations) for these extra doses.

Table 1 Converting anti-parkinson medications to levodopa equivalent daily dose

Drug Conversion factor

Immediate-release levodopa 1 9

Controlled-release levodopa 0. 975a

Carbidopa/levodopa extended-release capsules (Rytary) LD 0.5 9b

Entacapone (or Stalevo) LD 0.33 9c

Tolcapone LD 0.5 9c

Pramipexole (as salt) 100 9

Ropinirole 20 9

Rotigotine 30 9

Selegiline 10 mg (oral) 10 9

Selegiline 1.25 mg (sublingual) 80 9

Rasagiline 100 9

Amantadine 1 9

Apomorphine 10 9

LD levodopa dosea Based on the authors’ clinical experience, a conversion factor of 9 0.6–0.7 may be used for carbidopa/levodopa controlledrelease (e.g., Sinemet� CR, Merck & Co. Inc, Whitehouse Station, NJ)b Based on the conversion from carbidopa/levodopa immediate release to Rytary (Impax Laboratories, Inc., Hayward, CA)published by Pahwa and Lyons [25]c To calculate the total levodopa equivalent daily dose for catechol-O-methyl transferase (COMT) inhibitors (i.e., enta-capone, tolcapone), the total levodopa amount (including controlled-release levodopa if COMT inhibitor is given simul-taneously) should be calculated then multiplied by the appropriate value. For Stalevo� (Novartis Pharmaceuticals Corp.,East Hanover, NJ), the levodopa and COMT inhibitor should be split and calculated separatelyAdapted from Tomlinson et al. [24]

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The suggested volume of an individual extradose is 1 ml (20-mg levodopa), but this can bemodified at the clinician’s discretion. Forexample, a patient-specific approach may beused, wherein the extra dose is set at 25% of thehourly infusion rate. Typically, the pump isprogrammed to require a minimum of 2 hbetween extra doses, although some cliniciansopt for a smaller between-dose interval (e.g.,1 h). Allowing patients to self-administer extradoses gives clinicians the flexibility to start at aconservative LCIG dose, because patients canuse extra-dose ‘‘rescue’’ strategies until the

continuous dose can be increased by the clini-cian. If a patient requires multiple extra doseseach day, it suggests that the continuous LCIGdose needs to be increased.

SPECIAL CONSIDERATIONS

Non-local Patients

As mentioned above, in the interest of effi-ciency, patients who must travel a considerabledistance to the clinic may prefer to shorten the

Fig. 3 Calculating levodopa-carbidopa intestinal gel(LCIG) morning bolus dose and continuous infusion rate.Priming volume is the amount of LCIG needed to fillthe empty percutaneous endoscopic gastrojejunostomy

(PEG-J) tube. This is only required for the morning dosecalculation, as the tube will be full (or ‘‘primed’’) when thecontinuous infusion is begun

Table 2 Tips for tailoring levodopa-carbidopa intestinal gel dosing

Decrease the morning dose calculation multiplier from 0.8 to 0.6 for patients who are used to taking large oral levodopa

doses ([ 150 mg) with a long interval between the first and second doses

Offer patients the ability to increase or decrease their continuous infusion rate by 0.5 ml/h to decrease number of visits

needed

Offer customized extra-dose settings such as 1 ml every hour (or 2 h, 4 h, etc.)

Offer customized extra-dose strengths (e.g., 25% of hourly infusion rate) rather than the standard 1 ml (equivalent to

20-mg levodopa)

Factor regular use of extra doses into the calculation for maintenance-dose adjustment

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interval between PEG-J tube placement and theinitiation of LCIG. Although allowing time forhealing is preferred, LCIG treatment can bestarted within 24 h of the PEG-J procedure. InSweden, a pilot program evaluated the feasibil-ity of LCIG titration via remote video commu-nication-based telemonitoring from thepatient’s home. Remote monitoring was foundto be resource-efficient in the setting of naso-jejunal LCIG testing prior to permanent PEG-Jtube placement, a process that usually requires amultiple-day hospital stay [27]. Although nosuch remote monitoring has been assessed forpatients who proceed directly to PEG-J tubeplacement, nor has it been studied in the UShealthcare system, individual clinicians havereported success with monitoring of patients onLCIG via telephone.

Initiating Titration in the ‘‘Off’’ Versus‘‘On’’ States

Physicians have the option of initiating LCIG inthe ‘‘off’’ or ‘‘on’’ states. In the former case, thepatient would arrive at the clinic on the morn-ing of the first titration visit after missing onelevodopa dose (usually his or her morningdose). The clinician would then be able to assessthe effectiveness of the morning LCIG dose inthe clinic and ensure that the patient feels theeffect of the first dose, which normally occurswithin 30 min of administration.

The preference is that the patient arrive inthe ‘‘off’’ state to best begin the titration.Patients may come to the clinic having takentheir usual oral morning levodopa dose and bein the ‘‘on’’ state on arrival. If the patient is inthe ‘‘on’’ state when he or she presents to theclinic, LCIG is initiated at the continuousinfusion rate. It is important to note that thePEG-J tube will be empty at the start of thecontinuous dose in this scenario; therefore,timing of evaluations should include an allow-ance for pump priming. Using the example inFig. 3, at a rate of 3.8 ml/h, priming would takeapproximately 47 min. If the patient is in the‘‘off’’ state on arrival at the clinic, an extra doseis given via the LCIG pump and then the con-tinuous infusion is started. Alternatively, some

patients arriving in the ‘‘on’’ state start thepump with the morning bolus dose at home,then come to the clinic in the late morning orearly afternoon on the continuous infusion forassessment and dose adjustment. The initialcontinuous rate for these patients is determinedby either use of the standard conversion or acustom rate per clinician practice.

Concomitant Use of LCIG with Deep BrainStimulation

An increasing body of evidence supports the useof LCIG in patients receiving deep brain stim-ulation (DBS) who continue to experiencerefractory symptoms after programming opti-mization or long-term therapy [28–31]. As therequirement for oral medication increases inthese patients, LCIG may offer an advantageover oral levodopa because the fluctuatingplasma levels of orally administered levodopamay lead to severe dyskinesia in patients withsubthalamic nucleus DBS. DBS settings shouldbe kept stable during the initiation and titrationof LCIG, but over time, the relative contributionof DBS and LCIG to the patient’s symptomcontrol can be adjusted as needed.

PROGRAMING OPTIONS

The CADD-Legacy� 1400 portable infusionpump (Smiths Medical, Minneapolis, MN, USA)used in the delivery of LCIG has three settingsor ‘‘lock levels’’ that govern the degree to whichpatients can make changes to LCIG dosing. InLock Level 2, only the healthcare team canmake dosing adjustments. This allows thehealthcare provider to closely monitor thepatient, as any dose modification will require aclinic visit. This type of programming is alignedwith the method of care outlined in the pivotalUS LCIG study, in which all dosing adjustmentswere made at the investigator’s discretion;patients could not make changes to the infusionrate on their own [6]. In Lock Level 1, thehealthcare team can set a dosing range withinwhich patients may make small adjustments(generally 5–10% or less) to their morning- andcontinuous-dose rate. The benefit of using this

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option is that patients can immediately andautonomously respond to changes in theirmotor function, fine-tune their dosing regimen,reduce their dependence on the clinic staff, andgain awareness of their own treatment response.When using Lock Level 1, it is advisable to allowpatients to decrease dose and set the upper limitslightly above the anticipated optimal dose.Utilization of Lock Level 1 requires that thepatient and/or care partner have the cognitiveand motor skills necessary to adjust the pumpprogramming. In our experience, Lock Level 1 isfeasible for most patients. Lock Level 0 permitscomplete access to all programming and oper-ating features and is not typically allowed forpatient use.

It is important that any change in themorning- or continuous-dose rate made by thepatient, the number of extra doses used, andany need to pause the pump because of exces-sive dyskinesia are communicated to the clini-cian so that appropriate adjustments can bemade during the next clinic visit. Wearabledevices [32, 33] or patient diaries may provideadditional information on whether the optimalinfusion rate has been achieved and whetherthe goal of minimal ‘‘off’’ time and maximal‘‘on’’ time without bothersome dyskinesia hasbeen reached when the patient is in his or herhome environment.

PATIENT EDUCATIONAND TRAINING

The process of patient education and trainingbegins with the discussion of LCIG as a poten-tial treatment option, as either an immediateconsideration or a future possibility. Whenfeasible, the patient’s care partner should beinvolved in these discussions, particularly if heor she will be called on to assist in the setup andmanagement of the system and to provide reli-able information regarding symptoms (e.g.,‘‘on’’ and ‘‘off’’ time). The amount and type ofinformation relayed should align with thepatient’s stage in the process. For example, for apatient who has opted to initiate LCIG and isscheduled for PEG-J tube placement, a discus-sion with the patient and care partner should

provide procedural information and identifythe individuals involved in the care team andtheir responsibilities. This information will helpdirect the patient or care partner to the appro-priate contact should he or she have questionsor experience issues. Concerns regarding thePEG-J tube or wound site are best managed bythe proceduralist, whereas other questionsshould be directed to the neurologist andtreatment team or, as appropriate, DuoConnect,the manufacturer-sponsored patient andhealthcare provider support program.DuoConnect also provides nursing support viaphone and home health visits (if desired),which typically occurs before PEG-J tube place-ment, 24 h after the procedure, and on the dayfollowing LCIG initiation. This nursing educa-tion and support is a valuable resource duringthe titration process, particularly for patientswho initiate LCIG therapy for the first time athome with the morning bolus dose.

Instruction regarding the proper operation ofthe pump device is provided by the clinic staffduring the initial titration visit. If possible,introduction to a mock device prior to the ini-tial titration visit can help familiarize patientswith the pump. It is imperative that patientsand their care partners demonstrate theirunderstanding of the equipment and be able tooperate the pump prior to leaving the clinic onthe first titration visit.

SUBSEQUENT TITRATIONAND FOLLOW-UP

After the initial titration visit, the first follow-upvisit can be as early as the following day, butusually occurs after 2–6 weeks. For patients whohave been given the ability to make doseadjustments within a prespecified range (i.e.,Lock Level 1), the interval between the first andsecond visit may be extended. The goal of aclinic visit conducted the morning after theinitial titration is to ensure that the patient isusing the pump properly and to make anynecessary dose adjustments. Changes in dosingat this point are generally minor (\10%).Patients will arrive at the clinic in the ‘‘on’’ state

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and will be at the facility from as little as 30 minto a maximum of approximately 2 h.

During subsequent clinic visits, progressivelyless time will be spent discussing device ordosing issues and visits will revert back to reg-ular office visits. The only major change is thatthe medication regimen has become muchsimpler, with LCIG monotherapy being the rulerather than the exception. The number of extradoses being used on a regular basis should betaken into consideration. If there is a regu-lar/daily pattern in extra dose usage (e.g., C 5extra doses every day), increasing the continu-ous infusion rate is warranted. If, however, apatient uses multiple extra doses on occasionfor difficult days, the continuous dose may notneed to be adjusted, but consideration shouldbe given to broadening the range on the LockLevel 1 programming. Increasing the Lock Level1 dosing range is also advisable if concomitantanti-parkinson medications are being reducedor phased out. Much like oral levodopa treat-ment, in our clinical experience, decisionsregarding dosing and dose changes should alsofactor in tolerability, with clinicians queryingpatients or performing relevant assessmentsrelated to known carbidopa/levodopa sideeffects, such as somnolence, orthostatichypotension, signs of an impulse control dis-order, depression, suicidal ideation, neuropa-thy, symptoms of ischemic heart disease orarrhythmia, melanoma, and glaucoma [26].

ACHIEVING AN OPTIMAL LCIGDOSE

Over time, adjustments in LCIG dose will bewarranted, as they would be with any anti-parkinson medication. During the short term,reaching an optimal dose can be defined as thepoint at which dose adjustment becomes lessfrequent. In clinical trials, where patientassessment timing and titration methodologywere standardized, a stable LCIG dose wasachieved by most patients in approximately1 week [6, 10]. In clinical practice, once thepatient feels his or her motor fluctuations areadequately controlled and the practitioner seessufficient improvement on objective and

subjective measures, further dosing adjustmentscan be made as part of routine clinic visits(generally every 3–6 months). If a previouslyeffective infusion rate is no longer effective, theclinician may need to investigate to determineif the tube has moved from its initial placement.

CONCLUSIONS

Many approaches to provide continuous, non-pulsatile dopaminergic stimulation are beingpursued, including gastrointestinal pump-basedgels containing catechol-O-methyl transferaseinhibitors, levodopa pumps attached to atransdermal patch, and subcutaneous pump-based dopamine agonists [32]. The approval ofLCIG has added another treatment option tothe limited armamentarium for patients withadvanced PD. Utilization of LCIG is growing inthe US as clinicians gain familiarity with its use,but LCIG treatment still lags behind treatmentprovided in other countries where LCIG hasbeen available for more than 10 years. Percep-tions of titration complexity may inhibit clini-cians from pursuing LCIG therapy forappropriate patients. However, emerging clini-cal data and experience with LCIG outside theclinical trial setting have shown that titrationcan be easily managed on an outpatient basis.Moreover, flexibility in scheduling and indi-vidualized therapeutic regimens allow cliniciansto tailor the titration process to the patient andto their practices.

ACKNOWLEDGEMENTS

Funding. Development of this manuscript,including the Rapid Service Fee, was sponsoredby AbbVie, Inc., North Chicago, IL, USA. Abb-Vie participated in the interpretation of data,writing, reviewing, and approving the manu-script for publication.

Medical Writing and Other Editorial Assis-tance. Crystal Murcia, PhD, and Kelly M.Cameron, PhD, ISMPP CMPP, of JB Ashtin pro-vided medical writing and editorial support to

Adv Ther (2019) 36:2233–2246 2243

the authors in the development of this manu-script; medical writing support was funded byAbbVie.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published. Allauthors had full access to the articles reviewedin this manuscript.

Disclosures. Fahd Amjad has receivedresearch support/honoraria from AbbVie, TevaPharmaceutical Industries, UCB, Adamas Phar-maceuticals, US WorldMeds, Merz, and Lund-beck for consulting or serving on advisoryboards. Danish Bhatti has performed speak-ing/consulting activities for ACADIA Pharma-ceuticals, Teva Pharmaceutical Industries,AbbVie, Merz, and Adamas Pharmaceuticals.Thomas L. Davis has received research support/honoraria from AbbVie for consulting or servingon advisory boards. Odinachi Oguh hasreceived research support/honoraria from Abb-Vie and Adamas Pharmaceuticals for consultingor serving on advisory boards. Rajesh Pahwa hasreceived consulting fees from AbbVie, ACADIAPharmaceuticals, Acorda Therapeutics, AdamasPharmaceuticals, Cynapsus Therapeutics, Glo-bal Kinetics, Ionis Pharmaceuticals, Lundbeck,Neurocrine Biosciences, St. Jude Medical, TevaNeuroscience, UCB, and US WorldMeds. He hasreceived research grants from Acorda Thera-peutics, Adamas Pharmaceuticals, Avid Radio-pharmaceuticals, Boston Scientific, Cala Health,Cynapsus Therapeutics, Kyowa, NationalParkinson Foundation, NIH/NINDS, ParkinsonStudy Group, Pfizer, and US WorldMeds. Leo-nard V. Metman has received research support/honoraria from Abbott, AbbVie, Boston Scien-tific, and Medtronic for consulting or serving onadvisory boards. He has received research sup-port from AbbVie, Adamas Pharmaceuticals,Boston Scientific, Medtronic, Neuroderm Ltd,NIH, Pfizer, and US WorldMeds. Pavnit Kukrejais an employee of AbbVie. Inc., and may ownstock or stock options. Jorge Zamudio is an

employee of AbbVie. Inc., and may own stock orstock options.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand the authors’ clinical experience and doesnot involve any new studies of human or ani-mal subjects performed by any of the authors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercialuse, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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