Maximizing "On" Time: Longer-Lasting Levodopa Therapy Options for Parkinson's Disease
Parkinson’s disease (PD) is a progressive neurodegenerative disorder.1 As the disease progresses, the therapeutic window of levodopa narrows, such that previously effective doses of levodopa no longer provide adequate motor symptom control without negative side effects.2,3 Disease severity and other factors are speculated to result in emerging or increasing motor complications, which consist of motor fluctuations between alternating states when motor symptoms are well-controlled by levodopa (“On” time) and when motor symptoms reappear (“Off” time), as well as dyskinesias (involuntary muscle movements).3 The primary goal in treating PD with levodopa is to raise the troughs and lower the peaks in plasma levodopa level to minimize motor fluctuations and peak-dose dyskinesia.4
Levodopa therapy and “Good On” time: reframing the treatment goals of PD
Since the 1960s, the gold standard for treating PD has been levodopa (LD), with levodopa being the most widely used and efficacious treatment option for motor symptoms. Various formulations of LD have accounted for over half of the medications prescribed for PD in the United States between 2008 and 2016, and the American Academy of Neurology recommends levodopa as first-line therapy for early PD patients with motor symptoms.5,6
LD works by addressing low levels of dopamine in the brain caused by the loss of dopaminergic neurons associated with Parkinson’s.7 In 1975, carbidopa (CD) was added to LD to prevent conversion of LD to dopamine before it reaches the brain (premature conversion), effectively increasing LD’s half-life, efficacy, and tolerability.8,9
“Good On” time is the sum of periods where patients experience “On” time with no dyskinesia and “On” time with non-troublesome dyskinesia, and is most strongly correlated with patients’ perceived duration of good response to medication through the day.10 Unfortunately, as a patient’s PD progresses, the window of LD’s effectiveness is reduced, resulting in more “Off” time and “On” time compromised by disabling dyskinesias.2
LD’s shrinking therapeutic window and increasingly demanding dosing schedules
As the disease progresses, the therapeutic window of levodopa narrows, such that previously effective doses of levodopa no longer provide adequate motor symptom control.2 At the beginning of a dosing period, LD levels overshoot the therapeutic window, resulting in an “On” state with dyskinesia (sometimes referred to as “peak-dose dyskinesia”).11 At the end of a dosing period, patients experience a “wearing-off effect,” which is characterized by end-of-dose deterioration and recurrence of parkinsonian symptoms.11 Dopamine levels become increasingly dependent on oral LD as the disease progresses, causing the benefits of each dose to wear off more quickly.2 This narrowing therapeutic window leads to more unpredictable and inconsistent motor symptom management as the condition worsens.11
To combat the narrowing therapeutic window, HCPs usually adjust a patient’s CD/LD regimen by either increasing the size of each LD dose or dividing the total daily LD dose into smaller, more frequent doses; however, while these adjustments may be effective in the short-term, they are often met with poor long-term success.2,12 Physicians’ attempts at adjusting their patients’ medication to continue properly managing motor complications becomes a balancing act between trying to manage parkinsonism and preventing peak-dose dyskinesia.1,2
For immediate-release (IR) CD/LD, the therapeutic benefit of LD with advancing disease begins to approximate and eventually falls short of levodopa’s half-life (1.5 hours when co-administered with carbidopa).2,9 Some advanced PD patients take dopaminergic medications as often as 6-10 times a day.13 A meta-analysis found that, compared with once-daily dosing regimens, for patients living with chronic disease, timing adherence was 26.7%, 39.0%, and 54.2% lower for twice, 3-times, and 4-times daily dosing regimens, respectively.14
MYTH: Starting LD therapy early results in accelerated disease progression
I have heard some physicians say that one should start patients “low and slow” on levodopa medications. However, some studies assert that delaying LD therapy to delay development of motor complications or prevent disease progression, or initiating PD treatment with levodopa-sparing therapies like dopamine agonists or monoamine oxidase type B inhibitors (MAOBIs), is not justified.15-17 A follow-up of one of these studies even suggested that starting levodopa early may reduce the incidence of motor fluctuations.18
A 2014 study compared Parkinson’s disease patients from Italy with Parkinson’s disease with patients from Ghana who initiated levodopa treatment later in disease progression, on average. This analysis was intended to probe the contributions of disease progression and exposure to levodopa therapy, respectively, on the development of motor fluctuations and dyskinesias. The authors of this study concluded that these motor complications are associated not with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose.15
Another study published in The Lancet in 2014 by the PD MED Collaborative sought to determine whether starting treatment with LD-sparing therapy delays deterioration in patient-rated quality of life compared to LD alone, and which class of LD-sparing medication (dopamine agonists or MAOBIs) is best. This study’s results led these authors to conclude that there “seem to be no grounds for concerns that use of levodopa as first-line therapy results in worse long-term outcome.”17
A third study, the Levodopa in Early Parkinson’s Disease (LEAP) trial, aimed to determine whether levodopa has a disease-modifying effect to guide recommendations on levodopa initiation. In 2019, findings were published in the New England Journal of Medicine indicating that patients with early Parkinson’s disease whose CD/LD treatment regimens started sooner experienced no significant difference in motor fluctuations and dyskinesia in the first 80 weeks of treatment compared to a cohort with a delayed start.16 A post hoc analysis published in 2023 surveyed the same groups at 80 weeks, finding that there were fewer patients in the early-start group (23%) who experienced early signs of motor response fluctuations compared with the delayed start group (38%) (P<0.001).18
Altering LD treatment regimens to better treat PD
Over time, several oral CD/LD formulations have evolved from the original attempts to better address the needs of patients with PD.9 For example, controlled-release (CR) formulations have been developed in the hopes of decreasing motor complications by sustaining LD levels in the serum and eliminating extreme highs and lows seen with IR formulations.8 Unfortunately, patients with moderate to severe motor fluctuations did not experience quantitatively significant reductions in “Off” time compared to IR CD/LD in clinical trials.9,19
Another formulation called carbidopa-levodopa-entacapone (CLE) adds entacapone to the fold. Entacapone works by preventing LD from being degraded prematurely in the periphery and before it enters the brain, similarly to carbidopa albeit via a different mechanism.9 While CLE formulations extend LD’s half-life by nearly an hour and increase its exposure by 35%-40% compared to IR CD/LD, it has been shown to produce LD plasma profiles similar to CR CD/LD with higher LD fluctuations.9 Furthermore, the STRIDE-PD study found that patients taking CLE had a higher risk of developing dyskinesia compared to patients taking IR CD/LD (HR=1.29, P=0.04).20
Additionally, extended-release (ER) CD/LD capsules have been formulated to meet the need for better LD pharmacokinetics over existing preparations.9 By combining an IR CD/LD component and an extended-release component, which releases CD/LD gradually, levodopa levels are elevated quickly and subsequently sustained.21 In the ADVANCE-PD trial, patients who switched to extended-release medications experienced an increase in their “On” time without troublesome dyskinesia and a decrease in their “Off” time throughout the day compared to patients treated with IR CD/LD;22 in a post hoc analysis, ER CD/LD has also been shown to provide more "On" time per dose compared to IR CD/LD.23 Dosing conversion tools may help to ease the transition from immediate-release therapies to extended-release therapies.
In addition to oral therapies, treatment plans that use portable devices, like CD/LD pumps, have been devised to offer a reprieve from frequent dosing; these work well to continuously administer LD, but can have side effects like nodules on the skin.24 Currently available CD/LD pumps also require initial surgery, which may result in surgery or device-related complications.24 I have noticed they can be cumbersome, as they need to be carried at all times. These issues highlight some of the advantages of orally administered medications.
Future directions: achieving “Good On” time with longer-lasting treatment options
Looking to the future, the development of a robust, long-lasting, foundational oral CD/LD therapy that maximizes “Good On” time and has as small of a dosing burden as possible (eg, 1 or 2 doses per day) is a treatment goal I believe physicians should strive for in treating their patients with Parkinson’s disease. Longer-lasting LD therapies may help reduce dosing frequency, which has the potential to improve patient adherence.14 In my opinion, extended-release (ER) CD/LD may provide longer-lasting relief and simpler dosing and would be a step in the right direction.
Many patients and HCPs believe that a diagnosis of PD means that “Off” time is inevitable. I think one of our goals in treating people with PD should be to keep patients “On” continuously, with “Good On” time maximized as much as possible. As time progresses and more treatment options emerge, I hope that this goal becomes reality through better formulations with effective dosing, allowing patients to have more time to do what they love without disruption.
Sponsored by Amneal Pharmaceuticals LLC.
